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WO2001032213A1 - Promoteurs de regeneration hepatique et medicaments pour l'insuffisance hepatique - Google Patents

Promoteurs de regeneration hepatique et medicaments pour l'insuffisance hepatique Download PDF

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Publication number
WO2001032213A1
WO2001032213A1 PCT/JP2000/007686 JP0007686W WO0132213A1 WO 2001032213 A1 WO2001032213 A1 WO 2001032213A1 JP 0007686 W JP0007686 W JP 0007686W WO 0132213 A1 WO0132213 A1 WO 0132213A1
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WIPO (PCT)
Prior art keywords
liver
growth factor
vascular
vegf
factor
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PCT/JP2000/007686
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English (en)
Japanese (ja)
Inventor
Shotaro Sakisaka
Eitaro Taniguchi
Katsuhiko Matsuo
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Toagosei Co Ltd
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Toagosei Co Ltd
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Publication of WO2001032213A1 publication Critical patent/WO2001032213A1/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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • 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

Definitions

  • the present invention aims to promote liver regeneration and to treat liver dysfunction diseases such as alcoholic hepatitis, viral hepatitis, exacerbation of viral cirrhosis, and terminal cirrhosis, and to treat liver diseases associated with liver dysfunction.
  • liver dysfunction diseases such as alcoholic hepatitis, viral hepatitis, exacerbation of viral cirrhosis, and terminal cirrhosis
  • the present invention relates to therapeutic agents and methods for diagnosing liver regeneration ability, and belongs to medical and pharmaceutical technologies.
  • Angiogenesis the phenomenon of capillary endothelial cell proliferation, migration and tissue infiltration, is known to play an important role in physiological or pathological phenomena such as fetal growth, wound healing, and cancer cell proliferation.
  • Factors that induce angiogenesis include basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF), which act directly on vascular endothelial cells. ), Vascular endothelial growth factor / vascular permeability iactor (VEGF / VPF), platelet-derived endothelial cell growth factor (PD-ECGF), etc.
  • TGF- transforming growth factor-a
  • TGF- /? transforming growth factor- ⁇
  • TNF- ⁇ Angiogenin tumor necrosis factor-a
  • VEGF vascular endothelial cell growth factor / vascular permeability factor
  • liver failure is a condition in which the liver parenchyma that must function for some reason is reduced and the liver cannot maintain its function.
  • Liver failure is clinically divided into acute liver failure and chronic liver failure.
  • Acute hepatic failure is a condition in which an individual with no apparent history of liver disease suddenly develops severe hepatic impairment and liver failure.
  • Chronic liver failure is considered to be a condition in which a patient who has already had liver damage such as cirrhosis has developed liver failure for some reason.
  • Acute liver failure is a group of severe symptoms in which liver function is progressively impaired by various causes and causes jaundice, ascites, neuropsychiatric symptoms, blood clotting disorders, etc., and often results in poor prognosis.
  • the causes can vary, but include fulminant hepatitis, hepatic blood disorders, and obstructive jaundice.
  • acute liver failure is also considered as a condition in which a patient with chronic liver disease such as cirrhosis or hepatitis suddenly becomes metabolically deficient due to invasion such as surgery, bleeding, or infection.
  • hepatic failure is a state in which the liver function required by the living body cannot be fulfilled by all of the liver cells.
  • liver failure easily occurs even in a small invasion.
  • Hepatic coma is established by various factors such as so-called hepatic failure factor and abnormal amino acid metabolism due to hyperammonemia and hepatic parenchyma.
  • Therapies include administration of drugs that prevent or reduce the rise in blood ammonia, amino acid infusion, and plasma exchange.
  • hepatic failure associated with end-stage cirrhosis is largely irreversible and has no reliable treatment that can reproduce abolished liver function. Out of range.
  • the causes of such liver failure include alcohol-based drugs and drugs such as acetaminophen, isodiazide, methyldoba, drugs containing halogen (eg, carbon tetrachloride, chloroform, and halothane) and hepatitis.
  • drugs such as acetaminophen, isodiazide, methyldoba, drugs containing halogen (eg, carbon tetrachloride, chloroform, and halothane) and hepatitis.
  • Viruses eg, hepatitis B virus, hepatitis C virus, hepatitis D virus, etc.
  • hepatitis B virus hepatitis C virus, hepatitis D virus, etc.
  • liver has a long history, as taught in Prometheus myth It is known as a regenerative organ.
  • liver diseases such as acute hepatitis, chronic hepatitis, and cirrhosis
  • liver regeneration occurs following hepatocellular necrosis.
  • Fulminant hepatitis is a disease in which hepatic failure occurs due to rapid and widespread hepatocellular necrosis.
  • the survival rate is about 20%, and the prognosis is extremely poor.
  • it is important to prevent the progression of hepatocellular necrosis and promote liver regeneration.
  • VEGF 165 was intravenously administered to 70% of the hepatectomized rats, and PCNA (proliferating cell nuclear antigen) in the liver was measured by immunohistochemical staining and Westin blot.
  • PCNA proliferating cell nuclear antigen
  • VEGF inhibited the contraction of hepatic stellat cells cultured on collagen gel
  • VEGF could increase sinusoidal blood flow and protect liver damage due to ischemia.
  • this document does not suggest that VEGF protects against drug-induced liver damage.
  • the addition of VEGF suppressed the contraction of cultured stellate cells, indicating that VEGF may have a regulatory effect on sinusoidal blood.
  • VEGF expression in hepatocytes during ischemia was described.
  • VEGF acts on stellate cells to maintain sinusoidal blood flow (Mochida et al., Cell, 31 (3), 102-106 (1999)). Furthermore, since VEGF acts on activated stellate cells and suppresses cell contraction on collagen gel, it is estimated that VEGF acts protectively against hepatic microcirculation disorder (Mochida et al., Therapeutics) , 34 (4) 379-383 (2000) and cells, 31 (3), 192-106 (1999)). However, none of the documents suggests that VEGF can be used for the treatment or repair or treatment of liver failure, or for the protection of liver injury by drugs.
  • vascular endothelial cell growth factor Z vascular permeability Vascular growth factors such as factors (VEGF / VPF) are involved in liver regeneration, and the presence of vascular growth factors in the liver is important for treatment of liver failure and liver disease and diagnosis of regenerative ability And completed the present invention.
  • a liver regeneration promoting agent and a therapeutic agent for liver failure characterized by comprising a preparation containing a vascular growth factor such as vascular endothelial cell growth factor Z vascular permeability factor (VEGF / VPF). Is done.
  • the drug of the present invention can also be applied to the liver of a donor or a recipient after living donor liver transplantation.
  • vascular growth factors such as vascular endothelial cell growth factor / vascular permeability factor (VEGF / VPF) in the liver.
  • a treatment for a liver disease associated with hepatic dysfunction comprising a preparation containing a vascular growth factor, preferably VEGF, particularly preferably VEGF121.
  • Drugs are provided.
  • the liver disease associated with liver function abnormality in the present invention is a disease in which liver function is impaired, for example, acute and chronic hepatitis, liver fibrosis, or liver fibrosis caused by alcohol, other drugs, or pathogens. Examples include liver diseases such as cirrhosis. It also includes protection against liver damage by drugs that damage the liver.
  • vascular growth factor of the present invention include vascular endothelial cell growth factor / vascular permeability factor (VEGF / VPF) (hereinafter, simply referred to as “VEGF”).
  • VEGF vascular endothelial cell growth factor / vascular permeability factor
  • VPF vascular permeability factor
  • VEGF vascular endothelial cell growth factor / vascular permeability factor
  • the cDNA of the human VEGF gene has already been isolated and its nucleotide sequence has been determined, and the amino acid sequence has also been estimated. From this gene, four types of proteins with different numbers of amino acid residues (four types of amino acid residues: 121, 165, 189, and 206) were produced.
  • VEGF121 2 1 amino acid residue (VEGF121) and 1 It is said that one having 65 amino acid residues (VEGF165) is a mature protein (Ferrara N., et.al., Endocrine Reviews 13:18 (1992)).
  • VEGF121 lacks the 44 amino acids at the carboxyl terminus of VEGF165, but it has not been clarified whether there is a difference between VEGF121 and VEGF165 in the effects on vascular endothelial cells.
  • any of the above VEGFs can be used, but it is preferable to use VEGF121 or VEGF165.
  • the aforementioned angiogenesis factor can be used as the vascular growth factor of the present invention.
  • bFGF basic fibroblast growth factor
  • acidic fibroblast growth factor Acidic fibroblast growth factor, aFGF
  • platelet-derived endothelial cell growth factor PD-ECGF
  • TGF-a transforming growth factor- /?
  • TGF- Angiogenin
  • TNF- tumor necrosis factor
  • HGF hepatocyte growth factor
  • the preparation of the present invention is administered orally or parenterally.
  • Injection liquid for parenteral administration contains additives such as stabilizers, buffers, preservatives, and isotonic agents.
  • Tablets, capsules and the like usually contain a binder, an encapsulating agent, an excipient, a lubricant and the like generally used in those preparations.
  • the application amount varies depending on the disease state and the patient, but is generally about 5 ng to 1 mg per 1 kg of body weight.
  • FIG. 1 is a graph showing VEGF expression near the portal vein (periportal area) in the course of liver regeneration, based on VEGF immunochemical tissue staining.
  • FIG. 2 is a graph showing VEGF expression near the vein (perivenular area) in the course of liver regeneration, based on VEGF immunochemical tissue staining.
  • FIG. 3 is a graph showing the expression of Ki-67 in sinusoidal endothelial cells during the liver regeneration process accompanied by neutralization of VEGF by an anti-VEGF antibody or during VEGF administration.
  • FIG. 4 is a graph showing the expression of Ki-67 in hepatocytes during the liver regeneration process accompanied by neutralization of VEGF by an anti-VEGF antibody or during VEGF administration.
  • FIG. 5 is a graph showing the measurement results of serum liver function markers in the VEGF administered group and the VEGF non-administered group.
  • the Fischer rat (os) was subjected to the method of Higgins and Anderson et al. (Higgins GM, Anderson RM, Experimental pathology of the liver: 1. Restoration of the liver the white rat following partial surgical removal. , 1931; 12: 186-202).
  • VEGF immunochemical tissue staining After 0, 12, 24, 48, 96 and 168 hours after the 70% partial hepatectomy in section 11 above, the liver was collected from the rat and immunoassayed with anti-VEGF antibody. Staining was performed.
  • the rat liver was fixed with 10% formalin, embedded in paraffin, cut into sections of 3 mm in thickness, and silane-coated (si 1 an-coated) slides (DA KO, Sections were applied to Kyoto, Japan).
  • silane-coated (si 1 an-coated) slides (DA KO, Sections were applied to Kyoto, Japan).
  • endogenous protease was inactivated on the section with a 3% (v / V) hydrogen peroxide solution.
  • the section slide was immersed in 85% ethanol for 15 seconds, and further immersed in 75% ethanol for 15 seconds.
  • the sections contain 0.1% (V / V) 3-3'- one diam ino- one benzidine-tetrahydrochloride D AB) and 0.005% (/) hydrogen peroxide
  • the reaction was carried out at room temperature for 3 minutes in 0.1 Tris- ⁇ C1 buffer (pH 7.6). After washing with deionized water, observations were made with an optical microscope.
  • liver was collected from the rat and an anti-Ki-67 antibody was obtained. Immunohistochemistry staining was performed.
  • the deparaffinized section shown in the above section 12 was immersed in ethanol, and the endogenous passoxidase was inactivated by the method shown above.
  • the sections were autoclaved at 121 ° C. for 5 minutes and slowly brought to room temperature. After washing with T-PBS, the plate was immersed in Protein Block Serum-Free (DAK0) at room temperature for 3 minutes. The sections were reacted at 4 ° C. with an anti-Ki-67 monoclonal antibody (Immu notech, marseille, France) diluted 1 0 0-fold with T-PBS.
  • DAK0 Protein Block Serum-Free
  • anti-VEGF antibody Egret 10 fractions 200 per rat Rats were normal II Eg 1 ⁇ G fraction 200 g After administration to the rat via the tail vein, 48 hours later, immunohistochemical staining with an anti-Ki167 antibody was performed.
  • FIGS. 1 and 2 show the results of immunochemical tissue staining using anti-VEGF antibodies in liver sections.
  • VEGF was expressed in liver tissue over time after hepatectomy, peaked at 48 hours, and decreased thereafter. This suggests that VEGF is expressed during liver regeneration by liver resection and contributes to liver regeneration.
  • Ki-67 of sinusoidal endothelial cells in the group receiving anti-VEGF antibody Expression was significantly reduced as compared to the control (non-administration) group and the normal Egret IgG-administered group, and the proliferation of sinusoidal endothelial cells was higher than the control group and the normal Egret IgG-administered group. Is suppressed (Fig. 3). In other words, it indicates that the proliferation of sinusoidal endothelial cells was suppressed by suppressing the activity of VEGF.
  • VEGF plays an important role in the proliferation of sinusoidal endothelial cells and hepatocytes in the liver, and VEGF is required for rapid liver regeneration. It became clear that there was something.
  • Ki-167 in sinusoidal endothelial cells in the group to which VEGF was administered was significantly increased as compared to the control (non-administration) group and the normal rabbits IgG administration group. Liver regeneration is promoted as compared to the normal and heron IgG administration groups (Fig. 3). In other words, it shows that administration of VEGF proliferated hepatic sinusoidal endothelial cells.
  • VEGF can be used as a therapeutic drug for liver diseases associated with liver regeneration and liver failure.
  • VEGF is expressed in the liver and contributes to liver regeneration, so it is clear that the liver regeneration ability can be diagnosed by measuring the expression level of VEGF in the liver. It became.
  • SD Sprague-Dawley rats (oss) 10% carbon tetrachloride (olive oil) was administered to the 7-week-old back muscle twice a week for 10 weeks at lml / kg.
  • VEGF 121 Six weeks after the start of administration of 10% carbon tetrachloride (oliv oil), VEGF 121 was injected intravenously and the therapeutic effect of VEGF 121 on hepatic dysfunction was examined. .
  • VEGF121 adjusted to l ⁇ gZml with PBS was administered to 350 LZ mice via the rat tail vein.
  • 350 L / mouse of PBS was administered to the rats.
  • Administration of VEGF 121 and PBS was performed twice a week for 5 weeks.
  • liver protein was then used for liver function tests, such as total protein in serum, albumin, and thymoturbidity test (TTT).
  • TTT thymoturbidity test
  • ZTT Zincsulfateturbidityt est
  • GAT glut am icoxaloacetictrans am inase
  • GPT glut am icpyruvictrans am inase
  • ALP alkalinephosphatase
  • LDH lactatedehydr Ogenase
  • Table 1 shows the values for the amount of protein, albumin, TTT, ZTT, GOT, GPT, ALP, and LDH.
  • the values of total protein, albumin, TTT, ZTT, GOT, GPT, and ALP in the rat serum of the VEGF-administered group and the non-VEGF-administered group at 10 weeks after carbon tetrachloride administration are shown in Tables 2 and 3. This is shown in FIG. Table 3 shows the results of analysis of each liver function marker between the VEGF administration group and the PBS administration group using the t test.
  • GOT, GPT, ALP and LDH exceeded the normal values at both 5 weeks and 10 weeks after carbon tetrachloride administration, and abnormal liver function was caused by carbon tetrachloride. Had been raised. The degree was more abnormal at 10 weeks after the administration of carbon tetrachloride than at 5 weeks. In particular, in GOT and GPT, liver function was significantly deteriorated with a risk factor of less than 1%.
  • VEGF is used as a therapeutic drug for liver diseases with abnormal liver function.
  • VEGF non-administration group 6 6.52 0.306 4.05 0.138 0.53 0.103 0.63 0.151 356.33 149.71 383.17 250.42 679.50 189.33 4888.67 1184.27
  • VEGF group 6 6.35 0.243 3.87 0.151 0.37 0.052 0.40 0.089 147.67 56.92 132.33 70.31 438.17 113.40 1916.17 638.47 t-test; p-value 0.3207 0.0524 0.0054 0.0085 0.0096 0.0398 0.0231 0.0003
  • the present invention aims at promoting liver regeneration and treating liver dysfunction diseases such as alcoholic hepatitis, viral hepatitis, exacerbation of viral cirrhosis, and (end-stage cirrhosis), or liver diseases accompanied by abnormal liver function. It relates to therapeutic agents and methods for diagnosing liver regeneration ability, and is useful in medical and pharmaceutical technology.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne un procédé permettant de promouvoir la régénération hépatique; un nouveau procédé de traitement du foie atteint d'une insuffisance hépatique ou de maladies hépatiques associées à un dysfonctionnement hépatique ou faisant suite à une greffe hépatique; et un procédé permettant d'estimer la capacité de régénération hépatique. L'invention concerne plus précisément des promoteurs de régénération hépatique et des médicaments pour l'insuffisance hépatique ou les maladies hépatiques contenant des préparations renfermant des facteurs de croissance vasculaire tels que le facteur de croissance endothéliale vasculaire et/ou le facteur de perméabilité vasculaire (VEGF/VPF). Ces préparations se prêtent à une utilisation dans le domaine de la régénération hépatique à la suite d'une greffe hépatique essentielle. Fait aussi l'objet de cette invention un procédé d'estimation de la capacité de régénération hépatique consistant à mesurer la dose d'expression des facteurs de croissance vasculaire tels que le facteurs de croissance endothéliale vasculaire et/ou le facteur de perméabilité vasculaire.
PCT/JP2000/007686 1999-11-02 2000-11-01 Promoteurs de regeneration hepatique et medicaments pour l'insuffisance hepatique Ceased WO2001032213A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP11/311786 1999-11-02
JP31178699 1999-11-02
JP2000068367 2000-03-13
JP2000-68367 2000-03-13

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08310966A (ja) * 1995-05-18 1996-11-26 Agency Of Ind Science & Technol 繊維芽細胞成長因子キメラ蛋白質を含有する医薬組成物
JPH1048219A (ja) * 1996-08-02 1998-02-20 Toagosei Co Ltd 肝癌の検査方法及び検査薬
WO1998021335A1 (fr) * 1996-11-14 1998-05-22 Genetics Institute, Inc. Compositions de chordine
JPH10330284A (ja) * 1997-05-30 1998-12-15 Sumitomo Pharmaceut Co Ltd 肝細胞保護剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08310966A (ja) * 1995-05-18 1996-11-26 Agency Of Ind Science & Technol 繊維芽細胞成長因子キメラ蛋白質を含有する医薬組成物
JPH1048219A (ja) * 1996-08-02 1998-02-20 Toagosei Co Ltd 肝癌の検査方法及び検査薬
WO1998021335A1 (fr) * 1996-11-14 1998-05-22 Genetics Institute, Inc. Compositions de chordine
JPH10330284A (ja) * 1997-05-30 1998-12-15 Sumitomo Pharmaceut Co Ltd 肝細胞保護剤

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARTIFICIAL ORGANS, vol. 23, no. 2, February 1999 (1999-02-01), pages 146 - 152 *
DATABASE MEDLINE [online] February 1999 (1999-02-01), ELCIN Y.M. ET AL.: "Xenotransplantation of fetal porcine hepatocytes in rats using a tissue engineering approach", XP002936090, accession no. STN Database accession no. 1999151971 *
KEISHI WATANABE: "Idenshi sousa to shinsozai wo mochiita zouki kougaku", TANPAKUSHITSU KAKUSAN KOUSO, vol. 45, no. 8, June 2000 (2000-06-01), pages 68 - 74, XP002936092 *
RELF M.: "Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor and pleiotrophin in human primary breast cancer and relation to angiogenesis", CANCER RESEARCH, vol. 57, no. 5, 1997, pages 963 - 969, XP002936091 *

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