WO1998024467A1 - Medicaments contre l'hepatite fulminante - Google Patents

Medicaments contre l'hepatite fulminante Download PDF

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Publication number
WO1998024467A1
WO1998024467A1 PCT/JP1997/004478 JP9704478W WO9824467A1 WO 1998024467 A1 WO1998024467 A1 WO 1998024467A1 JP 9704478 W JP9704478 W JP 9704478W WO 9824467 A1 WO9824467 A1 WO 9824467A1
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Prior art keywords
hgf
liver
fulminant hepatitis
hepatitis
apoptosis
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PCT/JP1997/004478
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English (en)
Japanese (ja)
Inventor
Toshikazu Nakamura
Kunio Matsumoto
Kenichiro Kosai
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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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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 therapeutic agent for fulminant hepatitis disease. More specifically, the present invention relates to a therapeutic agent for fulminant hepatitis disease, which contains hepatocyte growth factor (HGF) as an active ingredient and is useful for treating and preventing fulminant hepatitis.
  • HGF hepatocyte growth factor
  • the liver is essential for living organisms with many physiological functions, such as gluconeogenesis, amino acid metabolism, lipid metabolism, plasma protein synthesis, secretion, bile production and secretion, detoxification, storage of energy sugars, and storage of vitamins.
  • gluconeogenesis amino acid metabolism
  • lipid metabolism lipid metabolism
  • plasma protein synthesis secretion
  • bile production and secretion detoxification
  • storage of energy sugars and storage of vitamins.
  • Fulminant hepatitis has a high fatality rate due to severe hepatopathy resulting from widespread necrosis and loss of hepatocytes caused by hepatitis virus and drugs.
  • severe hepatitis is a hepatic coma caused by severe liver dysfunction within about 8 weeks after the onset of hepatitis.
  • the prothrombin time is assumed to be 40% or less, including an acute type in which encephalopathy develops within 10 days after the onset and a subacute type which develops after 11 days. In the clinical picture, jaundice becomes severe within a few days after the appearance of hepatic inflammation, and consciousness is rapidly accompanied.
  • Serum total pyrilvin is often more than 1 O mg / dl, and serum transaminases show a remarkably high level at the beginning, but fall significantly within a few days.
  • the prothrombin value shows a remarkable decrease of less than 40%. It is often associated with cerebral edema, gastrointestinal bleeding, renal failure, intravascular coagulation, and systemic infections, and these complications often cause death. The prognosis is very poor, with a survival rate of 20--30% in Japan. There is no established treatment, and systemic management is required at present. Plasma exchange, transfusion transfusion, artificial liver assist devices, and glucagon / insulin therapy are provided.
  • Plasma exchange is performed at about 80% in Japan, but there is almost no difference in the survival rate between the treated group and the non-treated group.
  • Glucagon ⁇ insulin therapy has also been administered in 90 patients, but there is no difference in the overall survival rate between the treated group and the non-treated group.
  • Specialized amino acids are also administered in most cases, but there is little difference in survival between the two groups. In other words, 80% of patients undergoing plasma exchange, glucagon / insulin therapy, or specialty amino acid therapy, which are typical treatments in Japan during this period, are almost completely treated before such treatment is performed. This means that the survival rate has not improved, and the effect has to be very skeptical.
  • hepatitis within 8 weeks of coma and prothrombin time (PT) based on severe liver dysfunction within 8 weeks Defined as cases falling to 40%.
  • the liver is an organ with a large reserve, so if about 30% remain, it is usually well compensated. However, below that level, liver failure occurs, called liver failure.
  • the functions of the liver can be broadly divided into two major functions: the function of synthesizing substances and the function of metabolizing substances. Due to the dysfunction of the function, PT is reduced as an expression of reduced synthetic ability. PT is a test that measures the function of all five clotting factors, I, II, V, VI I, and X, all of which are made in the liver. Among them, factor VII, in particular, has a short half-life, halving in approximately a few hours. That is, when the synthesis ability decreases, the factor VII decreases from the beginning, and the PT time including the factor decreases. Second, coma occurs due to a decrease in detoxification metabolic function. The reason for setting the degree to I or higher was that the degree of I or higher was significant because the subjective judgment of the attending physician was entered in the case of I degree.
  • Hepatitis is the predominant disease in Japan. Hepatitis includes both viral and drug-induced hepatitis. In countries other than Japan, fulminant hepatitis is considered to be a disease in the category of acute hepatitis, but in Japan, there are many HBV carriers, and Fulminant cases are rarely seen. In the case of carriers, the time of onset of hepatitis is unknown, and chronic hepatitis can occur as long as it has the virus, and it can become fulminant.
  • the virus is slightly less than half and slightly more than half drug-active.
  • fulminant hepatitis is often caused by taking the paracetamol, or acetaminophen, an analgesic and antipyretic for suicide.
  • clinically experienced drug-induced liver injury is rather allergic hepatitis, in which case the dose is small enough to cause liver injury, and even if the causative drug is removed, the inflammation maintenance mechanism is already activated. However, liver damage cannot be terminated immediately.
  • hepatitis becomes fulminant there are two conditions for the mechanism by which hepatitis becomes fulminant. One is that many hepatocytes are infected. Another is that there is a very strong cytotoxic T lymphocyte immune response and vigorous hepatocyte destruction. In other words, fulminant hepatitis will not occur without two factors: many hepatocytes are infected, and the immune response is severe and hepatocyte destruction is severe. Based on this theory, the hepatitis A virus is cleared rapidly, so the elimination reaction takes place as the infection spreads to the point where it spreads, and it is eliminated without fulminating.
  • hepatitis C virus infection progresses to many hepatocytes, and it does not evoke a strong host immune response. It is understood that hepatitis B is the most susceptible to fulminant disease because of the intermediate spread of the virus and a fairly strong immune response.
  • necrosis is caused by pathological and non-physiological factors such as viruses, ischemia, and toxic substances, and morphologically shows the breakdown of the cell membrane after expansion of the cytoplasm, nucleus, and mitochondria.
  • Apoptosis is a physiological death, which is thought to be caused by the cell's comprehensive judgment of information by itself and the activation of a self-death device built into the cell. And nuclear It exhibits the morphological characteristics of enrichment and fragmentation and the biochemical characteristics of DNA fragmentation. Put another way, gene-controlled death is apoptosis, and non-genetically controlled death is necrosis.
  • fulminant hepatitis in Japan is viral and acute, with a fatality rate of more than 50% in the acute form and more than 90% in the subacute form. Moreover, it is a disease with a poor prognosis, and elucidation of the causes and development of effective treatments are urgently needed.
  • HGF has a suppressive, ameliorating or preventive effect on liver damage due to apoptosis, that is, Fas-induced apoptosis and the accompanying liver damage, and that HGF prevents fulminant hepatitis disease. It has been found useful in treatment.
  • HGF is a protein found as a factor for growing hepatocytes in vitro (Biochem. Biophys. Res. Commun., 122, 1450, 1984, Proc. Natl. Acad. Scad. USA, 83 , 6489, 1986, FEBS Letter, 22, 31
  • HGF which was discovered as a factor that specifically promotes hepatocyte proliferation, has shown various activities in vivo, such as tissue injury healing, based on recent research results by many researchers including the present inventors. Not only as a research target but also as a therapeutic drug for humans and animals. Expectations are gathering.
  • HGF is mainly produced by mesenchymal cells, and it has been revealed that a so-called paracrine mechanism has been established in which HGF is supplied from neighboring cells as needed. .
  • HGF production is also increased in uninjured organs such as the lungs, so it is considered that HGF is also supplied by the so-called endocrine mechanism.
  • HGF hepatitis disease
  • the present invention relates to a therapeutic agent for fulminant hepatitis disease, which comprises HGF as an active ingredient, and particularly for a fulminant hepatitis disease against fulminant hepatitis disease mainly caused by apoptosis. is there.
  • Another aspect of the present invention is a method for treating fulminant hepatitis disease, which comprises administering an effective amount of HGF; and use of HGF for producing a therapeutic agent for fulminant hepatitis disease.
  • FIG. 1 shows an example of a micrograph of a liver histopathological specimen of the mouse of Test Example 1.
  • a and B are micrographs at a magnification of 100 times
  • C is a micrograph at a magnification of 200 times.
  • Fig. 2 shows the liver histopathological specimen of the HGF-administered group in Test Example 2. It is a microscope picture.
  • A is a micrograph (200 ⁇ magnification) of a pathological tissue specimen of the liver of the mouse of Test No. 16
  • B is a micrograph of a pathological tissue specimen of the liver of the mouse of Test No. 19 ( ⁇ 1 magnification). 00 times).
  • FIG. 3 is a photomicrograph of a liver histopathological specimen of a saline-administered group (control) mouse (Test No. 14 mouse) in Test Example 2.
  • A is 100 times magnification and B is 200 times magnification.
  • HGF used in the present invention those prepared by various methods can be used as long as they are purified to the extent that they can be used as pharmaceuticals.
  • HGF human endothelial growth factor
  • extraction and purification from mammalian liver, spleen, lung, bone marrow, organs such as bone marrow, brain, kidney, placenta, blood cells such as platelets, leukocytes, plasma, serum, etc. See FEBS Letters, 224, 311, 1987, Proc. Natl. Acad. Sci. USA, 86, 5844, 1989, etc.).
  • HGF can be obtained by culturing primary cultured cells or cell lines that produce HGF, and separating and purifying them from cultures (culture supernatants, cultured cells, etc.).
  • a gene encoding HGF is inserted into an appropriate vector by a genetic engineering technique, inserted into an appropriate host, transformed, and the desired recombinant is obtained from the culture supernatant of the transformant.
  • HGF can be obtained (see, for example, Nature, 342, 440, 1989, Japanese Patent Application Laid-Open No. 5-111383, Biochem. Biophys. Res, Commun., 163, 967, 1989).
  • the above host cells are not particularly limited, and various host cells conventionally used in genetic engineering techniques, for example, Escherichia coli, Bacillus subtilis, yeast, filamentous fungi, plant or animal cells, and the like can be used. You.
  • HGF HGF-derived neurotrophic factor
  • rats are intraperitoneally administered with carbon tetrachloride, and the liver of a rat in a hepatitis state is extracted, excised, pulverized, and crushed.
  • Purify by standard protein purification methods such as gel column chromatography such as Sepharose and Heparin Sepharose and HPLC. be able to.
  • a gene encoding the amino acid of human HGF is incorporated into a vector such as sipper lipovirus virus DNA or the like, and the expression vector is used to express animal cells such as Chinese hamster ovary (CH0) cells. Cells, mouse C127 cells, monkey COS cells, etc. can be transformed and obtained from the culture supernatant.
  • a vector such as sipper lipovirus virus DNA or the like
  • the expression vector is used to express animal cells such as Chinese hamster ovary (CH0) cells.
  • Cells, mouse C127 cells, monkey COS cells, etc. can be transformed and obtained from the culture supernatant.
  • a part of the amino acid sequence may be deleted or replaced with another amino acid, or another amino acid sequence may be partially inserted, as long as it is substantially equivalent to HGF.
  • One or more amino acids may be bound to the N-terminal and / or the C-terminal, or the sugar chain may be similarly deleted, substituted and / or added.
  • the therapeutic agent of the present invention contains the above-mentioned HGF as an active ingredient, and the HGF suppresses, improves or prevents HGF against liver damage due to apoptosis by proliferating hepatic parenchymal cells as shown in the test examples described later.
  • HGF does not act on unaffected tissues but acts only on impaired tissues, it has the advantage that it is less likely to cause side effects. Therefore, the therapeutic agent of the present invention is effective for the treatment and prevention of fulminant hepatitis disease, particularly a lesion mainly composed of hepatic parenchymal cell proliferation.
  • the therapeutic agent of the present invention is useful for the treatment and prevention of various diseases caused by liver damage in various mammals (for example, mice, pigs, pigs, sheep, dogs, cats, etc.) in addition to humans. Applied.
  • the therapeutic agent of the present invention can be in various formulation forms (eg, liquid, solid, capsule, etc.), but generally, the active ingredient HGF alone or an injection and an inhalant, a suppository together with a conventional carrier are used. Or oral preparation.
  • the injection can be prepared by a conventional method. For example, after dissolving HGF in an appropriate solvent (for example, sterilized water, buffer solution, physiological saline, etc.), sterilize by filtering through a filter or the like. Then, it can be prepared by filling in a sterile container.
  • the HGF content in the injection is usually adjusted to about 0.0002-0.2 (w / v%), preferably about 0.001-0. L (w / v%).
  • Oral drugs include, for example, tablets, granules, powders, soft or hard capsules, solutions, emulsions, suspensions, It is formulated into a dosage form such as a lip-drop preparation, and these preparations can be prepared according to a conventional method of formulation.
  • Suppositories can also be prepared by a conventional method using a conventional base (for example, cacao butter, laurin butter, glycerinated gelatin, macrogol, witepsol, etc.).
  • Inhalants can also be prepared according to the conventional procedures for preparations.
  • the HGF content in the preparation can be appropriately adjusted depending on the dosage form, the disease to be applied, and the like.
  • a stabilizer is preferably added, and examples of the stabilizer include albumin, globulin, gelatin, glycine, mannitol, glucose, dextran, sorbitol, ethylene glycol and the like.
  • the preparation of the present invention may contain additives necessary for preparation, for example, excipients, dissolution aids, antioxidants, soothing agents, tonicity agents and the like.
  • a liquid preparation it is desirable to store it after freezing or freezing it to remove water. The freeze-dried preparation is used after reconstitution by adding distilled water for injection at the time of use.
  • the therapeutic agent of the present invention can be administered by an appropriate administration route according to the formulation.
  • it can be administered in the form of an injection to a vein, artery, subcutaneous, intramuscular, or the like.
  • the dosage is adjusted appropriately according to the patient's condition, age, weight, etc., but is usually 0.05 mg-500 mg, preferably lmg-10 Onig as HGF, which is divided into one or several times a day. Or continuous administration.
  • HGF which is an active ingredient, has an inhibitory, ameliorating, or preventing action on liver damage due to apoptosis, which is a cause of fulminant hepatitis, ie, Fas-induced apoptosis and liver damage accompanying the same. Therefore, the therapeutic agent of the present invention is effective in treating or preventing the above-mentioned fulminant hepatitis disease. Furthermore, since HGF acts only on the affected tissue, it is possible to obtain a drug with few side effects.
  • Jo-2 antibody Fas antibody
  • BALB / C mouse male 8 weeks old
  • ip intraperitoneally
  • ip 2 mice
  • Jo-2 antibody (2 mice) 2 mice
  • 2 mice 3 mice
  • control was administered iv (one mouse).
  • blood was collected from the tail vein 6 hours later, necropsy 24 hours later, and tissues were collected.
  • GPT, TP, ALB, and GOT were measured as liver function markers, a part of the liver was fixed in 10% formalin, and liver damage was determined by H & E staining under a microscope.
  • evaluation of apoptosis was performed.
  • a part of the liver was frozen, DNA was extracted, and DNA fragmentation analysis was performed by electrophoresis. The analysis of DNA extraction and DNA fragmentation is as follows.
  • Figure 1 shows an example of a micrograph of a histopathological specimen of the liver.
  • a and B are micrographs at a magnification of 100 times
  • C is a micrograph at a magnification of 200 times.
  • apoptosis induced by Jo-2 antibody administration occurs from hepatocytes around the Zone U portal vein, and increases in the amount of Jo-2 antibody.
  • Apoptosis extended from Zone 1 to Zone 2 and Zone 3 (hepatocytes around the central vein), and the degree of necrosis progressed. It was found that almost all hepatocytes in a wide area and diffusely fell into apoptotic necrosis.
  • HGF administration suppresses apoptosis liver injury
  • Jo - As 2 antibody dose and the mouse per 5 [mu] beta was administered intraperitoneally (ip) (nine mice).
  • ip intraperitoneally
  • HGF four mice
  • saline five mice
  • ip administration of HGF or saline was continuously performed at the time of antibody administration, 6 hours after antibody administration, and 12 hours after antibody administration.
  • Blood was collected from the tail vein 12 hours after administration of the Jo-2 antibody, and necropsy was performed 24 hours later to collect tissues.
  • GPT was measured as a liver function marker, a part of the liver was fixed in 10% formalin, liver damage was determined by H & E staining under a microscope, and apoptosis was evaluated.
  • FIG. 2 is a micrograph of a histopathological specimen of the liver of a mouse in the HGF administration group.
  • A is a micrograph of a histopathological specimen of the mouse of Test No. 16 (magnification: 200 times); 1 is a photomicrograph (magnification: ⁇ 100) of a liver histopathological specimen of the mouse of Test No. 19.
  • Fig. 3 is a photomicrograph of a liver histopathological specimen of a mouse in the saline administration group (control) (mice in Test No. 14). is there.
  • liver function GPT As shown in Table 2, all four mice treated with HGF showed low liver function GPT. In addition, as shown in Fig. 2, liver damage due to apoptosis was clearly suppressed. On the other hand, one mouse that received saline instead of HGF died 8 hours after the administration of Jo-2 antibody, but its liver tissue was diffuse and most of the hepatocytes exhibited necrosis due to apoptosis. And died of liver failure. The remaining 4 patients also showed high liver function GPT. Furthermore, as shown in Fig. 3, from the area around the portal vein (Zone 1) to the intermediate zone (Zone 2), the hepatopathological group of marked apoptosis of hepatocytes and the resulting cell death was observed. It was accompanied by severe hepatic injury with a woven image.
  • HGF was found to suppress apoptotic liver damage induced by Fas antibody.
  • aqueous solution containing 00 mg was aseptically prepared, dispensed into vials 1 ml at a time, lyophilized and sealed to obtain a lyophilized formulation :

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Zoology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Médicaments contre l'hépatite fulminante, qui contiennent comme principe actif le HGF (facteur de croissance des hépatocytes). Le HGF favorise la croissance des cellules du parenchyme hépatique et inhibe les troubles hépatiques liés à l'apoptose provoquée par les anticorps Fas. Ces médicaments sont donc utiles pour traiter et prévenir l'hépatite fulminante.
PCT/JP1997/004478 1996-12-05 1997-12-05 Medicaments contre l'hepatite fulminante Ceased WO1998024467A1 (fr)

Applications Claiming Priority (2)

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JP34263496A JP4463885B2 (ja) 1996-12-05 1996-12-05 劇症肝炎疾患治療剤
JP8/342634 1996-12-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment
EP1867339A4 (fr) * 2005-03-02 2010-05-26 Mitsubishi Tanabe Pharma Corp Agent antiviral
US10905742B2 (en) 2005-09-28 2021-02-02 Kagoshima University Application of heparin-binding epidermal growth factor-like growth factor for medical purposes

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1123709A1 (fr) * 1998-10-23 2001-08-16 Regeneron Pharmaceuticals, Inc. Agents preventifs/curatifs pour les maladies du foie
EP2649993B1 (fr) * 2010-12-09 2017-04-05 Maruishi Pharmaceutical Co., Ltd. Stabilisant d'acétaminophène
US9272018B2 (en) * 2011-04-18 2016-03-01 Kyoto University Acute hepatic insufficiency depressant and method for evaluating drug efficacy thereof
CN106456695B (zh) 2014-04-28 2019-11-12 卫材R&D管理有限公司 Hgf的冻干配制品
KR102275262B1 (ko) 2016-03-17 2021-07-12 에자이 알앤드디 매니지먼트 가부시키가이샤 활성 간세포 성장 인자(hgf)를 생성하는 방법
US20200341014A1 (en) * 2016-03-18 2020-10-29 Eisai R&D Management Co., Ltd. PD Marker of Hepatocyte Growth Factor (HGF)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04120097A (ja) * 1990-09-07 1992-04-21 Agency Of Ind Science & Technol 肝細胞増殖因子
JPH0640938A (ja) * 1992-07-17 1994-02-15 Toshiichi Nakamura Ｈｇｆ含有製剤
JPH0827026A (ja) * 1994-07-22 1996-01-30 Mitsubishi Chem Corp 肝疾患の予防・治療薬
JPH08501314A (ja) * 1992-09-16 1996-02-13 ジェネンテク，インコーポレイテッド Ｈｇｆによる肝臓障害に対する保護

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04120097A (ja) * 1990-09-07 1992-04-21 Agency Of Ind Science & Technol 肝細胞増殖因子
JPH0640938A (ja) * 1992-07-17 1994-02-15 Toshiichi Nakamura Ｈｇｆ含有製剤
JPH08501314A (ja) * 1992-09-16 1996-02-13 ジェネンテク，インコーポレイテッド Ｈｇｆによる肝臓障害に対する保護
JPH0827026A (ja) * 1994-07-22 1996-01-30 Mitsubishi Chem Corp 肝疾患の予防・治療薬

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NATURE, 1993, Vol. 364, OGASAWARA et al., "Lethal Effect of the Anti-Fas Antibody in Mice", pages 806-809. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment
EP1867339A4 (fr) * 2005-03-02 2010-05-26 Mitsubishi Tanabe Pharma Corp Agent antiviral
US10905742B2 (en) 2005-09-28 2021-02-02 Kagoshima University Application of heparin-binding epidermal growth factor-like growth factor for medical purposes

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JP4463885B2 (ja) 2010-05-19
JPH10167982A (ja) 1998-06-23

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