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WO1995019789A1 - Agent de prevention ou de traitement des troubles moteurs - Google Patents

Agent de prevention ou de traitement des troubles moteurs Download PDF

Info

Publication number
WO1995019789A1
WO1995019789A1 PCT/JP1995/000057 JP9500057W WO9519789A1 WO 1995019789 A1 WO1995019789 A1 WO 1995019789A1 JP 9500057 W JP9500057 W JP 9500057W WO 9519789 A1 WO9519789 A1 WO 9519789A1
Authority
WO
WIPO (PCT)
Prior art keywords
preventive
remedy
spinal cord
disorder
dysfunction
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1995/000057
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Okajima
Yuji Taoka
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
GC Biopharma Corp
Original Assignee
Green Cross Corp Japan
Green Cross Corp Korea
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 Green Cross Corp Japan, Green Cross Corp Korea filed Critical Green Cross Corp Japan
Publication of WO1995019789A1 publication Critical patent/WO1995019789A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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

Definitions

  • AT- is a type of glycoprotein belonging to a2 globulin, and its amount is 65,000-68,000, indicating that it has protease inhibitory activity in the blood coagulation system. It strongly inhibits the clotting activity of thrombin.
  • AT-I [[, which has such pharmacological action, has been used for the purpose of correcting coagulation abnormalities 73 ⁇ 41, and specifically for the treatment of generalized 'tt intubation coagulation ⁇ ! (D I C).
  • An object of the present invention is to provide a novel drug utilizing the unexplained action of AT-II. That is, it aims to use AT-II for a new medical use. Disclosure of the invention
  • the present invention has an effect of improving ⁇ dysfunction and tissue disorder, and have achieved the present invention. That is, the present invention relates to a method for preventing agricultural dysfunction using AT-m: And spinal injury prediction.
  • the AT-m used in the present invention is not particularly limited as long as it is derived from humans and is optionally purified to the extent possible.
  • AT-m from human whole blood, human serum, serum or It can be purified from serum or the like compressed from coagulated blood.
  • the blood to be abolished is particularly preferable if it is negative for HBs3 ⁇ 4H and anti-HIV antibody, and is less than twice as strong as GTP.
  • Starting materials for preparing ⁇ — ⁇ include, for example, fraction IV-1, fraction IV, supernatant I or supernatant ⁇ + ⁇ ( ⁇ ⁇ 5 8 4) Equalized.
  • Examples of the method for purifying AT- ⁇ include the methods disclosed in JP-A-48-35017 and JP-B-59-7693, and Kaihei 1-275600), anion exchanger treatment (Japanese Unexamined Patent Publication No. 2-47177), and the like.
  • AT-II is based on the cell culture method (for example, see Japanese Patent Application Laid-Open No. 57-500768), and the fetal culture (for example, see Japanese Patent Application Laid-Open No. 58-162,529). It may be prepared according to the publication. Also, a commercially available AT-III preparation (eg, trade name: Neuart Z Co., Ltd. Midori Cross, etc.) can be used.
  • AT-m which is 3 ⁇ 4 ⁇ of the present invention, has a protective action against spinal cord injury and spinal cord in mammals such as humans, dogs, dogs, dogs, mice, rats, etc.
  • ⁇ 3 ⁇ 4 ⁇ has the effect of improving dysfunction.
  • 3 »dysfunction refers to a condition that causes abnormalities in taste function due to disorders of the central nervous system or peripheral nerves.
  • spinal cord disorders eg, spinal cord injury, Specifically, for example, paraplegia, paralysis, hemiplegia, paraplegia and the like can be mentioned.
  • the thread job disorder refers to a failure or a functional disorder of each painter, for example, an obstacle of mi-woven. Therefore, AT-m is useful as an aza dysfunction disorder, preventive reversal of thread work disorder, ⁇ ⁇ preventive cure U and circulatory wound preventive cure J, especially Mi function caused by ⁇ ⁇ or spinal cord injury. Useful as prevention and Z or reversal of conditions involving at least one disorder or disorder.
  • AT- ⁇ has an improving effect on circulatory-induced threadwork disorder or S3 ⁇ 4 function disorder (eg, paraplegia) that occurs as a complication in thoracic aneurysm surgery.
  • AT-III also has the effect of improving complications associated with injuries, such as thrombosis and pulmonary thrombosis.
  • the preventive remedy ij of the present invention usually includes pharmacologically acceptable additives (eg, carriers, adjuvants, diluents, etc.), stabilizers and the like used in the adjuncts, as long as the object of the present invention is not violated.
  • pharmacologically acceptable additives eg, carriers, adjuvants, diluents, etc.
  • stabilizers and the like used in the adjuncts, as long as the object of the present invention is not violated.
  • essential ingredients may be blended.
  • additives and stabilizers include sugars, for example, crafts such as glucose and fructose, Js such as sucrose, pulp li tang, maltose, sugar alcohols such as mannitol and sorbitol; citric acid, malic acid, tartaric acid, etc.
  • Organic acids or salts thereof for example, sodium salt, potassium salt, calcium salt
  • amino acids such as glycine, aspartic acid, and glutamic acid or salts thereof (for example, sodium salt)
  • polyethylene glycol, polyp Surfactants such as ropylene glycol, its derivatives (eg, pull mouth nick), and polyoxyethylene sonolebitan fatty acid esters (eg, Tween); heparin, albumin and the like.
  • the preparation of the present invention is prepared by mixing AT AT with the above, and prepared in the form of powder, liquid, granules, tablets, capsules, syrups, tablets, etc., and administered orally or parenterally Is done. Preferably, it is a mode of intravenous administration.
  • This product is prepared by preparing AT-m as a ⁇ ⁇ 3 ⁇ 4 ⁇ product with a pharmacologically acceptable excipient, and dissolving it at the time of use into a fiber formulation or a liquid formulation.
  • a preparation can be prepared as about 1 to 100 AT-DI single fe / ml sickle by using distilled water or sterile purified water, if necessary, more preferably a physiologically isotonic salt concentration and physiological Is adjusted to a preferable pH value (pH 6 to 8).
  • the dose may be selected according to the condition, body weight, animal species, etc.
  • AT-HI is usually 1 to 100 single fe kg body weight Z days, preferably 10 to 100 days.
  • ⁇ 500 units kg body weight Z day is administered once or several times a day.
  • the titer of AT-IE corresponds to the amount of AT-m contained in 1 ml of normal human plasma.
  • Spinal cord R was obtained by opening the chest of a rat (body weight 300-400 g) and ligating the thoracic ⁇ ⁇ pulse (5th thoracic vertebral level) for 30 minutes.
  • AT-1 ⁇ was given intravenously 30 minutes before ligation (250 single fe / kg body weight) or 15 minutes after ligation (500 single & / kg body weight), hind limbs »function, neutrophil accumulation in spinal cord and tissue Using the amount (measured as MP0 activity 12 hours after ligation) as a target, the preventive and therapeutic effects described in // function disorders and the pre-treatment effects in thread fiber disorders were examined.
  • the impairment was determined 24 hours after the ligation procedure, and the degree of impairment was objectively evaluated using the following Talob (Tar 10 V) evaluation method.
  • Table 1 shows the dysfunction score and the percentage of paraplegia. AT- ⁇ Insect (pre- and post-treatment) markedly improved. table 1
  • M P0 myelin peroxidase
  • MPO is an index of the degree of local disability.
  • the MP0 level in the damaged spine was measured 12 hours after spinal cord injury by an absorbance measurement method (wavelength: 460 nm). By administering AT-II, MPO was reduced to about 1Z2 and the degree of disability was reduced.
  • the outflow in one tissue was reduced by about 40% by pre-administration of AT-II.
  • a The protective effect of ⁇ — ⁇ was offset by the combined use of heparin. Since heparin and DEG-Xa had no effect, it may be due to effects other than blood anticoagulant effect ⁇
  • AT- ⁇ was administered after injury: the effect of ⁇ , ie, the therapeutic effect of AT-III administration was examined.
  • spinal wound rats were prepared according to the method of Experimental Example 2. The experiments were performed in the following four groups, and their effects were compared.
  • DAT-HI pre-administration group AT- ⁇ administered intravenously 30 minutes before spinal cord injury at a dose of 250 / kg / body weight
  • AT-IE dose AT- ⁇ body administration Group
  • AT-IE dose 250 mg, intravenously administered 30 minutes after spinal cord injury at Z kg body weight
  • 4 AT—Wm AT—Wm.
  • Administration group (AT_m dose 500 Intravenous administration was performed 30 minutes after the spinal cord injury was given with a kg body weight.) The effect was confirmed and iffi was performed according to the method of Experimental Example 1.
  • MP 0 was measured and confirmed in the same manner as in Experimental Example 1 for the behavior of MP 0 at the site of the injury when A ⁇ -m was administered after the injury.
  • spinal injured rats were prepared according to the method of Experimental Example 2. The experiment was performed in the following three groups, and the effects were compared. 1 Normal rats 1 ⁇ »administration group (spine cord injury group), 3 AT—— post-treatment group ( ⁇ — ⁇ administration dose 250 alone ⁇ intravenous administration 30 minutes after spinal cord injury with i kg body weight) . Table 4 shows the results. With AT-HI administration, MPO was reduced to about 12 and the damage was reduced.
  • the acute toxicity (LDBO) did not differ by ⁇ in mice and rats, and was 15,000 single fekg body weight Ui for both intravenous and oral administration and 20000 single & kg body weight for subcutaneous administration. In monkeys (males), intravenous administration was 6000 units Zkg body weight J ⁇ ⁇ .
  • heparin sepharose prepared in advance at physic: ft ⁇ z was introduced into a fiber-coated column, and AT-m was adsorbed to the column.
  • the column was washed with 0.4 M sodium chloride to remove impure proteins, and then 2.0 M sodium chloride was passed through a force ram to collect the eluted portion.
  • Sodium citrate was added to the aqueous solution of AT- ⁇ to a concentration of 0.6 M, the pH was adjusted to 7.8, and heat treatment was performed at 60 ° C for 10 hours, followed by 0.9% chloride.
  • the sodium was subjected to fiber dialysis overnight while dialysis was performed to obtain 1- (wZv) XlYmL of AT-III, and filtered or centrifuged as necessary to obtain a transparent liquid.
  • AT- ⁇ has the effect of improving dysfunction and threadwork disorder in mammals.
  • spinal cord ⁇ ilX is effective against thread fiber disorder or »function disorder due to spinal cord injury, such as paraplegia Has an improving effect. Therefore, ⁇ — ⁇ is useful as 3 «/ function impairment prevention and return ij, Itoshiori Chapter P harm prevention and prevention and spinal cord injury prevention» J C that is 57

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne un agent de prévention ou de traitement des troubles moteurs, un agent de prévention ou de traitement des lésions tissulaires, un agent de prévention ou de traitement de l'ischémie spinale, ainsi qu'un agent de prévention ou de traitement des blessures spinales, contenant chacun de l'antithrombine III d'origine humaine comme principe actif. L'antithrombine III a pour effet de traiter les lésions tissulaires et les troubles moteurs, chez les mammifères, en particulier les troubles dus à l'ischémie spinale ou à une blessure spinale, par exemple la paralysie.
PCT/JP1995/000057 1994-01-21 1995-01-20 Agent de prevention ou de traitement des troubles moteurs Ceased WO1995019789A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP513194 1994-01-21
JP6/5131 1994-01-21
JP6/50813 1994-03-22
JP5081394 1994-03-22
JP6/256508 1994-10-21
JP25650894 1994-10-21

Publications (1)

Publication Number Publication Date
WO1995019789A1 true WO1995019789A1 (fr) 1995-07-27

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ID=27276612

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/000057 Ceased WO1995019789A1 (fr) 1994-01-21 1995-01-20 Agent de prevention ou de traitement des troubles moteurs

Country Status (1)

Country Link
WO (1) WO1995019789A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001015723A1 (fr) * 1999-09-01 2001-03-08 Mitsubishi Pharma Corporation Medicaments pour la prevention ou le traitement de lesions ischemiques ou de lesions de reperfusion ischemique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH024717A (ja) * 1988-06-22 1990-01-09 Green Cross Corp:The アンチトロンビン−３製剤
JPH04108738A (ja) * 1990-08-29 1992-04-09 Kita Kiyoshi アンチトロンビン溶剤の使用方法
JPH06256213A (ja) * 1993-03-03 1994-09-13 Green Cross Corp:The ヒト由来アンチトロンビン−ｉｉｉの医薬用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH024717A (ja) * 1988-06-22 1990-01-09 Green Cross Corp:The アンチトロンビン−３製剤
JPH04108738A (ja) * 1990-08-29 1992-04-09 Kita Kiyoshi アンチトロンビン溶剤の使用方法
JPH06256213A (ja) * 1993-03-03 1994-09-13 Green Cross Corp:The ヒト由来アンチトロンビン−ｉｉｉの医薬用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001015723A1 (fr) * 1999-09-01 2001-03-08 Mitsubishi Pharma Corporation Medicaments pour la prevention ou le traitement de lesions ischemiques ou de lesions de reperfusion ischemique

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