US20010051146A1 - Agent for preventing and/or treating multiple organ failure - Google Patents

Agent for preventing and/or treating multiple organ failure Download PDF

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Publication number
US20010051146A1
US20010051146A1 US09/180,599 US18059999A US2001051146A1 US 20010051146 A1 US20010051146 A1 US 20010051146A1 US 18059999 A US18059999 A US 18059999A US 2001051146 A1 US2001051146 A1 US 2001051146A1
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Prior art keywords
tcf
multiple organ
organ failure
hgf
agent
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Hirohiko Arisawa
Hiroaki Masunaga
Hiromi Ogawa
Kanji Higashio
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Daiichi Pharmaceutical Co Ltd
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Daiichi Pharmaceutical Co Ltd
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Assigned to SNOW BRAND MILK PRODUCTS, CO., LTD. reassignment SNOW BRAND MILK PRODUCTS, CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MASUNAGA, HIROAKI, ARISAWA, HIROHIKO, HIGASHIO, KANJI, OGAWA, HIROMI
Publication of US20010051146A1 publication Critical patent/US20010051146A1/en
Assigned to DAIICHI PHARMACEUTICAL CO., LTD. reassignment DAIICHI PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SNOW BRAND MILK PRODUCTS CO., LTD.
Priority to US10/317,011 priority Critical patent/US7306791B2/en
Abandoned legal-status Critical Current

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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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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 agent for preventing and/or treating multiple organ failure.
  • Onset or exacerbation of multiple organ failure can be classified into the following 3 categories with respect to mechanism: (1) Parallel induction of several organ disorders due to the same factor; (2) Induction of a specific organ dysfunction due to disorder of an organ; and (3) Participation of an iatrogenic factor. Excessive insults due to severe trauma or major surgeries, infectious diseases, shock etc. directly or through various kinds of mediator participate in the onset or deterioration of multiple organ failure by mechanism (1). In the case of multiple organ failure accompanied with organ disorder due to trauma or primary hepatic insufficiency, participation of mechanism (2) through organ correlation mechanism will largely contribute to the onset or deterioration thereof.
  • mechanism (3) medical care carried out during intensive care or care to correspond with an organ disorder may result in the other organ disorder.
  • these 3 mechanisms participate to the development or deterioration of disorder in a complexed manner.
  • the prognosis of patients of multiple organ failure is generally very poor and, in fact, the survival rate is low as 20-30% in spite of a wide variety of corresponding treatment.
  • the present inventors eagerly investigated to look for an agent for preventing and/or treating multiple organ failure and found that multiple organ failure caused by burn, disseminated intravascular coagulation (DIC), circulatory failure, hemorrhagic shock, infectious disease, acute pancreatitis, ischemic disorder, hepatorenal syndrome, gastrointestinal hemorrhage, nutritional metabolic failure, terminal cancer, acquired immunodeficiency syndrome (AIDS), deterioration of systemic conditions due to radiation affection and cachexia etc.
  • DIC disseminated intravascular coagulation
  • hemorrhagic shock infectious disease
  • acute pancreatitis ischemic disorder
  • hepatorenal syndrome hepatorenal syndrome
  • gastrointestinal hemorrhage gastrointestinal hemorrhage
  • nutritional metabolic failure terminal cancer
  • acquired immunodeficiency syndrome (AIDS) acquired immunodeficiency syndrome
  • an object of the present invention is to provide an agent for preventing and/or treating multiple organ failure comprising TCF-II or HGF as an effective ingredient.
  • the present invention relates to an agent for preventing and/or treating multiple organ failure comprising TCF-II or HGF as an effective ingredient.
  • FIG. 1 shows the protective effect of TCF-II on endotoxin-induced multiple organ failure in example 4.
  • FIG. 2 shows the protective effect of HGF on endotoxin-induced multiple organ failure in example 5.
  • FIG. 3 shows the protective effect of TCF-II on dimethylnitrosamine-induced multiple organ failure in example 7.
  • FIG. 4 shows the protective effect of TCF-II on thioacetamide intoxication-induced multiple organ failure in example 8.
  • FIG. 5 shows the protective effect of TCF-II on acetaminophen intoxication-induced multiple organ failure in example 8.
  • FIG. 6 shows the protective effect of TCF-II on multiple organ failure caused by mercuric chloride-induced renal insufficiency in example 9.
  • FIG. 7 shows the protective effect of TCF-II on tripsin-induced multiple organ failure in example 10.
  • FIG. 8 shows the protective effect of TCF-II on burn-induced multiple organ failure in example 11.
  • FIG. 9 shows the protective effect of TCF-II on burn-induced multiple organ failure in example 12.
  • FIG. 10 shows the protective effect of HGF on burn-induced multiple organ failure in example 13.
  • ⁇ represents the TCF-II or HGF treatment group and ⁇ represents the vehicle treatment group.
  • the agent of the present invention for preventing and/or treating multiple organ failure can be useful for preventing and/or treating the development from burn, disseminated intravascular coagulation (DIC), circulatory failure, hemorrhagic shock, infectious disease, acute pancreatitis, ischemic disorder, hepatorenal syndrome, gastrointestinal hemorrhage, nutritional metabolic failure, terminal cancer, acquired immunodeficiency syndrome (AIDS), deterioration of systemic conditions due to radiation affection and cachexia etc.
  • DIC disseminated intravascular coagulation
  • hemorrhagic shock infectious disease
  • acute pancreatitis ischemic disorder
  • hepatorenal syndrome hepatorenal syndrome
  • gastrointestinal hemorrhage gastrointestinal hemorrhage
  • nutritional metabolic failure terminal cancer
  • acquired immunodeficiency syndrome (AIDS) acquired immunodeficiency syndrome
  • AIDS acquired immunodeficiency syndrome
  • TCF-II which is an effective ingredient of the present invention was found by the present inventors and a known glycoprotein derived from human fibroblast having the following characteristics:
  • TCF-II can be obtained by adsorbing culture medium of human fibroblast on an ion exchange column then purifying the elute by affinity chromatography (WO 90/10651) or by genetic engineering manipulation (WO 92/01053).
  • TCF-II which is an effective ingredient of the present invention can be derived from fibroblast or produced by genetic engineering manipulation using microbial or other cell as based on the genetic sequence described in patent application WO 90/10651. Further, TCF-II obtained by genetic engineering manipulation described in WO 92/01053 can be also used. TCF-II with different carbohydrate chain or without carbohydrate chain due to difference of host cell or microbial organism can be also used.
  • TCF-II obtained by these methods can be concentrated and purified by usual isolation and purification method. For example, precipitation with organic solvent, salting-out, gel permeation, affinity chromatography using monoclonal antibody, electrophoresis can be exemplified. Purification by affinity chromatography using monoclonal antibody can be carried out using monoclonal antibody described in a Japanese unexamined laid open patent application No.97(1993). The obtained TCF-II can be lyophilized or kept frozen.
  • Substance having the same activity as TCF-II can be used as the agent of the present invention.
  • hepatocyte growth factor HGF; Japanese unexamined laid-open patent application No.22526 (1988)
  • SF Scattered Factor
  • HGF which is an effective ingredient has an activity proliferating hepatic sell, was isolated from the blood of a patient with fulminating hepatitis and is unknown protein with the following characteristics (Japanese patent No.2564486):
  • HGF can be obtained by heating plasma at 56° C. for about 15 minutes, taking precipitated fraction at the ammonium sulfate concentration of 1.1-1.2 M, followed by purification using gel permeation and ion exchange chromatography such as DEAE anion exchange chromatography.
  • HGF can be obtained by genetic engineering manipulation using HGF cDNA (BRRC 163, 967-973, 1989, or Japanese unexamined laid open patent application No.97(1993)).
  • the agent of the present invention for preventing and/or treating multiple organ failure can be administered intravenously, intramuscularly or subcutaneously.
  • These pharmaceutical preparation can be prepared according to a known pharmaceutical preparation method and, if necessary, pH conditioner, buffer and/or stabilizer can be added thereto.
  • Dose of the present agent can be different depending on the severness of symptom, health conditions, age, body weight of a patient. Though the dose will not be restricted, pharmaceutical preparation comprising 0.6mg-600mg-TCF-II/day, preferably 6 mg-60 mg-TCF-II/day, for one adult person can be administered at once or more.
  • the dose of HGF can be nearly the same as that of TCF-II.
  • Administration as described above can prevent multiple organ failure caused by various kinds of mechanism described before or alleviate symptom thereof.
  • Culture medium 750 L was concentrated by ultrafiltration using membrane filter (MW 6,000 cut; Amicon) and purified by 5-steps chromatography, that is, CM-Sephadex C-50 (Pharmacia), Con-A Sepharose(Pharmacia), Mono S column (Pharmacia), Heparin-Sepharose (Pharmacia) to yield purified TCF-II.
  • This TCF-II had the same molecular weight and isoelectric point as described before.
  • TCF-II cell transformed with TCF-II gene was cultured and purified TCF-II was obtained. That is, transformed Namalwa cell was cultured and 20 l of culture medium was obtained. This culture medium was treated by CM-Sephadex C-50 chromatography, Con-A Sepharose CL-6B chromatography and finally HPLC equipped with a Mono S column to yield about 11 mg of recombinant TCF-II.
  • This TCF-II had also the same molecular weight and isoelectric point as described before.
  • Expression vector of HGFcDNA was constructed by inserting 2.4 kb fragment of transcription unit of mouse dihydrofolate reduce 7 tase (DHFR) into Nhel site of plasmid pcDNA1 and ,frther, inserting 2.3 kb of HGFcDNA cloned by Miyazawa (BBRC 163, 967-973, 1989) into the downstream of Cytomegalovirus (CMV) promoter.
  • the constructed HGFcDNA expression vector ( ⁇ g and pSV2 neo 1 ⁇ g were cotransfected into Namalwa cell by liposome intervened transfection method using lipofectin.
  • HGF highly producing cell line was cultured in 2 L roller bottle containing 1 L DMEM medium including 5% bovine serum for 7 days. Culture was carried out using 20 roller bottles (2 rpm)and 21 L of culture medium was obtained. The culture medium obtained like this contained 4 mg/L HGF. According to a modified method of Higashio (Higashio et. al., vol.
  • TCF-El 100 ⁇ gtmouse obtained in example 2 was administered intravenously to 7 weeks old male ICR mice (25 mice/l group) twice daily for 5 days (only at the final day, once a day).
  • the control group was treated with the vehicle (citric acid buffer solution with pH 6.03, hereinafter the same solution was used as control group).
  • lethal dose of endotoxin LPS- E. coli; 20 mg/kg, Difco laboratories
  • the survival rates thereof was shown in FIG. 1.
  • TCF-II was confirmed to show an excellent protective effect on endotoxin-induced multiple organ failure.
  • HGF (100 ⁇ g/mouse) obtained in example 3 was administered intravenously to 7 weeks old male ICR mice (15 mice/l group) twice daily for 5 days (only at the final day, once a day).
  • the control group was treated with the vehicle (citric acid buffer solution with pH 6.03).
  • lethal dose of endotoxin (LPS- E - coli; 20 mg/kg, Difco laboratories) was administered intravenously.
  • the survival rates thereof was shown in FIG. 2.
  • TCF-II was confirmed to show an excellent protective effect on multiple organ failure caused by endotoxin-induced cachexia.
  • TCF-II 100 ⁇ g/mouse was administered intravenously to 7 weeks old male ICR mice (25 mice/1 group) twice daily for 5 days (only at the final day, once a day). The control group was treated with the vehicle. At 6 hours after the final administration, lethal dose of 0.15% dimethynitrosoamine (DMN) (vehicle:physiological saline solution, 0.1 ml/10 g body weight, Tokyo-kasei-kogyo) was administered intravenously. The results of clinical examination of mice at 24 hours after the onset was shown in table 2 and the the survival rates thereof was shown in FIG. 3.
  • DN dimethynitrosoamine
  • TCF-II 100 ⁇ g/mouse was administered intravenously to 7 weeks old male ICR mice (25 mice/1 group) twice daily for 5 days (only at the final day, once a day).
  • the control group was treated with the vehicle.
  • lethal dose of thioacetamide (600 mg/kg, Wako-junyaku) or acetaminophen (800 mg/kg, Sigma) was administered.
  • the survival rates thereof was shown in FIG. 4 and FIG. 5.
  • survival rates after day 4 or later of vehicle administered group was 12% (3/25 mice), that of TCF-II administered group was 93% (23/25 mice).
  • TCF-II 100 ⁇ glmouse was administered intravenously to 7 weeks old male ICR mice (25 mice/1 group) twice daily for 5 days (only at the final day, once a day).
  • the control group was treated with the vehicle.
  • lethal dose of mercuric chloride (Wako-junyaku) was administered intravenously.
  • the survival rates thereof was shown in FIG. 6. Though the survival rates after 4 days of vehicle administered group was 8% (2/25 mice), the whole mice of TCF-II administered group survived.
  • TCF-II was confirmed to show an excellent protective effect on multiple organ failure caused by mercuric chloride-induced.
  • TCF-II Vehicle or 1 mg/kg TCF-II was administered intravenously to 7 weeks old male Wister rats (50 rats/1 group) twice daily for 6 days (only once a day on the final day). At 6 hours after the final administration, 25% burn (250° C., 30 sec.) was made on shaved back with a heating plate (twaki-glass). The survival rates thereof was shown in FIG. 8. And the results of clinical examination at 4 hours after burn treatment was shown in table 3. Decrease of circulating volume of Plasma (increase in Ht value, decrease in total protein, decrease in albumin) and hepatic derangement were observed and onset of multiple organ failure caused by burn shock was confirmed (Table 3).
  • TCF-II 20 ⁇ g human serum albumin 100 mg
  • An agent for preventing and/or treating multiple organ failure comprising TCF-II or HGF as an effective ingredient will be provided by the present invention.
  • the agent for preventing and/or treating multiple organ failure of the present invention will be useful for preventing and/or treating the development from burn, disseminated intravascular coagulation (DIC), circulatory failure, hemorrhagic shock infectious disease, acute pancreatitis, ischemic disorder, hepatorenal syndrome, gastrointestinal hemorrhage, nutritional metabolic failure, terminal cancer, acquired immunodeficiency syndrome (AIDS), deterioration of systemic conditions due to radiation affection and cachexia etc. to multiple organ failure.
  • DIC disseminated intravascular coagulation
  • circulatory failure hemorrhagic shock infectious disease
  • acute pancreatitis ischemic disorder
  • hepatorenal syndrome hepatorenal syndrome
  • gastrointestinal hemorrhage gastrointestinal hemorrhage
  • nutritional metabolic failure terminal cancer
  • acquired immunodeficiency syndrome (AIDS) acquired immunodeficiency syndrome
  • AIDS acquired immunodeficiency syndrome

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US09/180,599 1997-03-11 1998-03-11 Agent for preventing and/or treating multiple organ failure Abandoned US20010051146A1 (en)

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JP7437297 1997-03-11
JP15764597A JP4006058B2 (ja) 1997-03-11 1997-05-30 多臓器不全予防及び／又は治療剤

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NZ298141A (en) 1994-12-27 2000-12-22 Snow Brand Milk Products Co Ltd Treating lipid metabolism disorder using TCF-II
DE69531673T2 (de) 1994-12-27 2004-07-08 Daiichi Pharmaceutical Co., Ltd. Tcf mutante
JPH08231418A (ja) 1995-02-24 1996-09-10 Mitsubishi Chem Corp 腸疾患治療剤
AU4953796A (en) 1995-03-15 1996-10-02 Sanyko Company, Limited Dipeptide compounds having ahpba structure
EP0823256A4 (de) 1995-04-21 2000-06-21 Mitsubishi Chem Corp Mittel zur vorsorge und/oder heilmittel zur behandlung von ischämischen erkrankungen
JPH10194986A (ja) 1996-06-10 1998-07-28 Snow Brand Milk Prod Co Ltd 移植肝機能改善・再生促進剤
JP3887435B2 (ja) 1996-07-12 2007-02-28 第一製薬株式会社 スフェロイド形成促進剤
JPH1068400A (ja) 1996-08-28 1998-03-10 Tetsuo Taira 液体を押し出すボトルポンプ及びその方法と製造方法
JP4006058B2 (ja) 1997-03-11 2007-11-14 第一三共株式会社 多臓器不全予防及び／又は治療剤
AU734766B2 (en) * 1997-03-14 2001-06-21 Atlas Pharmaceuticals Inc. Agent for preventing and/or treating cachexia
JP3961064B2 (ja) 1997-03-28 2007-08-15 第一製薬株式会社 腎疾患予防及び／又は治療剤
JPH1129493A (ja) 1997-07-14 1999-02-02 Snow Brand Milk Prod Co Ltd 放射線障害予防及び／又は治療剤
JPH11269091A (ja) 1998-03-19 1999-10-05 Snow Brand Milk Prod Co Ltd 敗血症予防及び／又は治療剤

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CA2252711A1 (en) 1998-09-17
US7306791B2 (en) 2007-12-11
AU6309298A (en) 1998-09-29
DE69839621D1 (de) 2008-07-31
WO1998040096A1 (en) 1998-09-17
EP0914829B1 (de) 2008-06-18
JPH10310535A (ja) 1998-11-24
AU725441B2 (en) 2000-10-12
JP4006058B2 (ja) 2007-11-14
EP0914829A1 (de) 1999-05-12
EP0914829A4 (de) 2004-06-16
US20030153489A1 (en) 2003-08-14
ES2308802T3 (es) 2008-12-01
ATE398460T1 (de) 2008-07-15

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