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WO2003105819A1 - Remede de type quinone pour hepatopathie - Google Patents

Remede de type quinone pour hepatopathie Download PDF

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Publication number
WO2003105819A1
WO2003105819A1 PCT/JP2003/007491 JP0307491W WO03105819A1 WO 2003105819 A1 WO2003105819 A1 WO 2003105819A1 JP 0307491 W JP0307491 W JP 0307491W WO 03105819 A1 WO03105819 A1 WO 03105819A1
Authority
WO
WIPO (PCT)
Prior art keywords
menatetrenone
active ingredient
liver cancer
recurrence
agent
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/JP2003/007491
Other languages
English (en)
Japanese (ja)
Inventor
小池　幸宏
白鳥　康史
椎名　秀一郎
寺谷　卓馬
小尾　俊太郎
佐藤　新平
浜村　啓介
赤松　雅俊
建石　良介
藤島　知則
菅田　美保
吉田　晴彦
石川　隆
川瀬　建夫
小俣　政男
水田　敏彦
安武　努
江口　有一郎
藤本　優
尾崎　岩太
和田　郁子
山本　匡介
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.)
Eisai Co Ltd
Original Assignee
Eisai Co Ltd
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
Priority claimed from JP2002204709A external-priority patent/JP2004067513A/ja
Application filed by Eisai Co Ltd filed Critical Eisai Co Ltd
Priority to CA002488880A priority Critical patent/CA2488880A1/fr
Priority to AU2003277184A priority patent/AU2003277184B2/en
Priority to BR0311781-2A priority patent/BR0311781A/pt
Publication of WO2003105819A1 publication Critical patent/WO2003105819A1/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61P35/00—Antineoplastic agents
    • 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 liver disease containing menate trenone as an active ingredient, and more particularly to a therapeutic agent for improving prognosis of liver cancer.
  • HC C hepatocellular carcinoma
  • PVI Portal Venous Invasion
  • DCP Des-y-Carboxy Prothrombin
  • PI VKA-II Protein Induced by Vitamin K Absence or Antagonist
  • VK Vitamin K Absence or Antagonist
  • an object of the present invention is to provide an excellent therapeutic and prophylactic agent for liver disease. .
  • the present invention has been found for the first time to be capable of administering an oral VK-II preparation to DCP-producing HCC patients, contributing to suppression of PVI development and improvement of prognosis after HCC treatment, and suppression of recurrence after treatment of liver cancer. is there.
  • the above object is achieved by a therapeutic / prophylactic agent for liver disease containing menatetrenone as an active ingredient.
  • the liver disease is liver cancer.
  • the therapeutic or prophylactic agent is characterized by being the liver cancer mosquito Des- ⁇ -Carboxy Prothrombin (DCP) -positive menopausal cancer.
  • DCP Des- ⁇ -Carboxy Prothrombin
  • the therapeutic / prophylactic agent is characterized by improving the prognosis after treating liver cancer.
  • the therapeutic / preventive agent is an agent for suppressing the occurrence of tumor invasion (PVI) in the portal vein.
  • an agent for suppressing the occurrence of tumor invasion (PVI) in a portal vein comprising menatetrenone as an active ingredient.
  • the above-mentioned object is achieved by an agent for improving survival rate after treatment for liver cancer, comprising menatetrenone as an active ingredient.
  • the above-mentioned object is achieved by an agent for suppressing recurrence of hepatocellular carcinoma containing menatetrenone as an active ingredient.
  • the above-mentioned object is achieved by a method for preventing invasion of portal vein tumor (PVI), which comprises administering to a patient an effective amount of a drug containing menatetrenone as an active ingredient.
  • PVI portal vein tumor
  • a method for suppressing recurrence of hepatocellular carcinoma which comprises administering to a patient an effective amount of a drug containing menatetrenone as an active ingredient.
  • a method for regulating the amount of DCP in blood which comprises administering to a patient an effective amount of a drug containing menatetrenone as an active ingredient.
  • menatetrenone for producing a PVI generation inhibitor
  • menatetrenone for suppressing the recurrence of hepatocellular carcinoma.
  • a therapeutic / prophylactic agent for liver disease containing vitamin Ks as an active ingredient.
  • the therapeutic agent for liver disease containing menatetrenone according to the present invention is excellent in suppressing the occurrence of PVI in liver diseases, particularly in DCP-positive liver cancer, and is also excellent in improving the prognosis after treatment for liver cancer. Furthermore, the therapeutic agent for liver disease containing menatetrenone according to the present invention is extremely useful for suppressing recurrence of liver cancer after treatment.
  • BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a flowchart for selecting patients.
  • FIG. 2 is a graph showing changes in serum DCP levels.
  • FIG. 3 is a graph showing a change in the incidence of PVI.
  • Figure 4 is a graph showing the change in survival rate.
  • FIG. 5 is a graph showing the effect of VK-II administration on the suppression of liver cancer recurrence (50% recurrence).
  • FIG. 6 is a graph showing results of only HCV cases in a test for confirming the effect of VK-II administration on the suppression of liver cancer recurrence (50% recurrence).
  • FIG. 7 is a graph showing the results of a test for confirming the effect of VK-II administration on the suppression of liver cancer recurrence (50% recurrence) when local recurrence was excluded.
  • FIG. 8 is a graph showing the results of the effects of VK-II administration on the suppression of liver cancer recurrence (50% recurrence) when relapsed cases within 6 months are excluded.
  • FIG. 10 is a graph showing the results of analyzing DCP before treatment and at the time of recurrence.
  • Liver cancer develops at a high rate from chronic hepatitis and cirrhosis, which are the subjects of the present invention, and once it develops, it recurs at a high rate after treatment.
  • hepatitis C or B may cause cirrhosis and recur after tumor resection.
  • the prognosis after such treatment for liver cancer can be extremely effectively improved (that is, prevention or treatment of recurrence).
  • liver cancer with poor prognosis The occurrence of PVI, one of the recurrent forms, can be suppressed very effectively.
  • Menatetrenone used in the present invention chemical name 2 - methyl one 3 - tetra- Bed les two Honoré-1, 4 - in Na oice onboard emissions (2-methl-3-tetraprenyl -l, 4-naphthoquinone) Yes Yes
  • the structural formula is shown below.
  • Menatetrenone is a yellow crystalline or oily substance that has no smell and taste and is easily decomposed by light. It is hardly soluble in water. Menatetrenone is also called vitamin K-II (VK-II), and its pharmacological action is that glutamate residues have physiological activity during the process of protein synthesis of blood coagulation factors (prothrombin, VII, IX, X). It is involved in the lipoxylation reaction when converted to ⁇ -lipoxyglutamic acid, promotes hepatic synthesis of normal prontrobin, etc., activates the hemostatic mechanism of the living body, and exerts a physiological hemostatic action. Things.
  • Menatetrenone which is an active ingredient of the medicament of the present invention, may be an anhydride or may form a hydrate. Menatetrenone may have a crystalline polymorph, but is not limited thereto. Any one of the crystalline forms may be single or a mixture of crystalline forms. Furthermore, metabolites generated by decomposing the menatetrenone according to the present invention in vivo are also included in the claims of the present invention.
  • Menatetrenone used in the present invention must be manufactured by a known method. As a typical example, according to the method disclosed in Japanese Patent Application Laid-Open No. 49-55650, it can be easily produced, and can also be easily obtained from a synthesis maker. Menatetrenone is also available as capsules, injections, and other preparations.
  • the drug according to the present invention may use menatetrenone as it is, or a known pharmaceutically acceptable carrier (eg, excipient, binder, disintegrant, lubricant, coloring agent, flavoring agent) , Stabilizing agents, emulsifiers, absorption enhancers, surfactants, pH regulators, preservatives, antioxidants, etc.) and ingredients commonly used as raw materials for pharmaceutical preparations.
  • a known pharmaceutically acceptable carrier eg, excipient, binder, disintegrant, lubricant, coloring agent, flavoring agent
  • Stabilizing agents emulsifiers, absorption enhancers, surfactants, pH regulators, pre
  • components such as vitamins, amino acids and the like may be added.
  • the formulation form include tablets, powders, fine granules, granules, capsules, syrups, suppositories, injections, ointments, cataplasms and the like.
  • menatetrenone capsules are available under the trade name K2 Capsule (made by Eisai Co., Ltd.) and Graquet Ichiryu Posel (made by Eisai Co., Ltd.). It can be obtained as Meitetsu N Note (manufactured by EZ Corporation).
  • the drug containing menatetrenone according to the present invention is useful for treating and preventing liver diseases.
  • the preferred dose of menatetrenone is usually from 10 to 200 mg Z days, more preferably from 30 to 135 mg Z days.
  • test examples of the present invention will be described, but these are illustrative, and the present invention is not limited to these test examples. Those skilled in the art can make various modifications to the claims described in the present specification as well as the following test examples, and such modifications can be implemented. Is included. -Test example 1
  • Vitamin K formulation perfurin oral
  • the treatment group was a group to which VK-II (trade name: Grake I: manufactured by Eisai Co., Ltd.) was orally administered at 45 mg Z days after liver cancer treatment, and the non-treatment group was to receive VK-II. There is no group.
  • follow-up Following treatment for liver cancer, a follow-up test (follow-up) was performed.
  • a follow-up study was performed on outpatients with an ultrasonography (abdominal echo) every 3 months (receiving ultrasonography every 3raonths), a CT scan every 6 months, a CT scan every 6 months, and alf a-fetoprotein and DCP were measured every month at the highest level.
  • Table 2 shows the patient profiles. There were no significant differences in each clinical parameter between the treated and untreated groups.
  • Treatment group 60
  • Non-treatment group 61
  • P Age 66.9 ⁇ 7.0 67.3 ⁇ 7.5.8 Sex male / female
  • HCV / non HCV 50/10 52 /9.8.81
  • Tumor suspicion mm
  • Figure 2 is a graph showing changes in serum DCP levels.
  • the solid line is The treatment group is shown, and the dotted line represents the non-treatment group.
  • DCP levels decreased in both the treated and untreated groups. Thereafter, DCP levels in the treated group were similar for 12 months, while DCP levels in the untreated group gradually increased.
  • the PVI incidence and survival of each group were statistically treated. In other words, use the Cox Proportional Hazard model! / Log-rank method. The average observation period was 12 ⁇ 8 months.
  • a case in which hepatocellular carcinoma was diagnosed from March 1999 to March 2001, and was determined to be completely dying (or curative resection) by contrast-enhanced CT after its treatment 6
  • One case was entered, and one case was added to the VK-II group and the even group to the non-treated group (control group).
  • the administration group was orally administered a VK-II preparation (trade name: Graquet-I; Eisai Co., Ltd.) at a dose of 45 m / day.
  • Contrast-enhanced CT or MR I was performed every three months, and the time to recurrence was statistically analyzed. That is, comparison was performed by the K ap 1 an-Meier method (Log rank test), and the risk ratio of recurrence (Risk Ratio) was analyzed using the Cox proportional hazard model.
  • FIG. 5 is a graph showing the effect of VK-II administration on the suppression of liver cancer recurrence (50% suppression). As shown in FIG. 5, the period up to 50% recurrence was 26 months in the VK-II administration group, whereas it was 10 months in the control group.
  • the cumulative recurrence rate of hepatocellular carcinoma was calculated for HCV cases (hepatitis C cases) only.
  • the cumulative recurrence rate of liver cancer was significantly suppressed in the VK-II-administered group compared to the control group.
  • FIG. 6 is a graph showing the results of a test for confirming the effect of VK-II administration on the suppression of liver cancer recurrence (50% recurrence) when HCV cases are limited. As shown in FIG. 6, the time to 50% recurrence was 26 months in the VK_II administration group, whereas it was 10 months in the control group.
  • the risk ratio for recurrence of liver cancer was 0.329 in the VK-II-administered group, which was about one-third that of the control group, especially in HCV cases.
  • administration of VK-II reduced the risk to 0.210, reducing the risk by about one-fifth.
  • Fig. 7 is a graph showing the results of excluding cases of local recurrence in a test confirming the effect of VK-II administration on the suppression of liver cancer recurrence (50% inhibition) (VK-II administration group: 29 cases). , Non-administration group: 2 2 cases).
  • Fig. 8 is a graph showing the effect of VK-II administration on the suppression of recurrence of liver cancer (50% inhibition), excluding relapse cases within 6 months (VK-II Administration group: 31 cases, non-administration group: 22 cases). As shown in FIGS. 7 and 8, also in these cases, the cumulative recurrence rate of liver cancer was significantly suppressed in the VK-II-administered group as compared to the control group.
  • FIG. 10 is a graph showing the results of analyzing DCP before treatment and at the time of recurrence. As shown in FIG. 10, in the recurrence cases of the VK_II administration group, all DCP were negative, there were no side effects, and no shedding cases.
  • VK_II The effect of VK_II according to the present application on invasion and metastasis of liver cancer cells was investigated in vitro.
  • the effect on the invasion ability was examined by an invasion assay using HepG2 cells and a matrigenoretensioner. As a result, it was confirmed that the number of cells that passed through Matrigel decreased in a concentration-dependent manner by the addition of VK-II.
  • the effect of VK-II on the expression of extracellular matrix degrading enzyme (MMP) was examined by Western blotting as to the effect on metastatic ability. Examination of the protein expression of MMP-1 and MMP-3 when VK-II was added to hepatoma cells revealed that the expression was suppressed. Based on these data, it can be considered that VK-II suppresses invasion and metastasis of hepatocellular carcinoma cells, although this is in vitro data.
  • the therapeutic agent for liver disease containing menatetrenone according to the present invention is excellent in the effect of suppressing the occurrence of PVI against liver diseases, particularly DCP-positive liver cancer, and also excellent in improving the prognosis of the therapeutic agent for liver cancer. I have.
  • the therapeutic agent for liver disease containing menatetrenone according to the present invention is extremely useful for suppressing recurrence of liver cancer after treatment.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Afin d'obtenir un remède contre une hépatopathie notamment par inhibition du début d'une perfusion veine-porte (PVI), l'invention concerne un excellent remède/préventif contre une hépatopathie contenant en tant que principe actif la menatetrènone. Ce remède/préventif contre une hépatopathie est efficace contre le cancer du foie, en particulier, le cancer du foie positif à DCP (des-γ-carboxyprothrombine). Le remède/préventif ci-dessus décrit contre une hépatopathie contenant de la menatetrènone en tant que principe actif exerce un effet remarquable améliorant le pronostic suivant une thérapie du cancer du foie, présentant ainsi également un excellent effet en tant qu'inhibiteur de récurrence de cancer du foie.
PCT/JP2003/007491 2002-06-12 2003-06-12 Remede de type quinone pour hepatopathie Ceased WO2003105819A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002488880A CA2488880A1 (fr) 2002-06-12 2003-06-12 Remede de type quinone pour hepatopathie
AU2003277184A AU2003277184B2 (en) 2002-06-12 2003-06-12 Quinone-type remedy for liver disease
BR0311781-2A BR0311781A (pt) 2002-06-12 2003-06-12 Agente terapêutico a base de quinona para hepatopatia

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
JP2002172133 2002-06-12
JP2002-172133 2002-06-12
JP2002172162 2002-06-13
JP2002-172162 2002-06-13
JP2002204709A JP2004067513A (ja) 2002-06-12 2002-07-12 キノン系肝疾患治療剤
JP2002-204709 2002-07-12
JP2002245178 2002-08-26
JP2002-245178 2002-08-26
PCT/JP2002/009640 WO2003105818A1 (fr) 2002-06-12 2002-09-19 Remedes a base de quinone destines a des maladies du foie
JPPCT/JP02/09640 2002-09-19

Publications (1)

Publication Number Publication Date
WO2003105819A1 true WO2003105819A1 (fr) 2003-12-24

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Family Applications (1)

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PCT/JP2003/007491 Ceased WO2003105819A1 (fr) 2002-06-12 2003-06-12 Remede de type quinone pour hepatopathie

Country Status (4)

Country Link
AU (1) AU2003277184B2 (fr)
BR (1) BR0311781A (fr)
CA (1) CA2488880A1 (fr)
WO (1) WO2003105819A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065671A1 (fr) * 2004-01-06 2005-07-21 Eisai Co., Ltd. Prophylactique servant a empecher l'apparition d'un cancer du foie, comprenant un compose quinone en tant qu'ingredient actif
WO2005077351A1 (fr) * 2004-02-12 2005-08-25 Eisai Co., Ltd Remèdes de type quinones pour des maladies pulmonaires
WO2007091557A1 (fr) * 2006-02-10 2007-08-16 National University Corporation Nagoya University Préparation pharmaceutique pour le traitement ou la prévention du cancer du foie

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63185921A (ja) * 1987-01-28 1988-08-01 Takeda Chem Ind Ltd 肝疾患治療剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63185921A (ja) * 1987-01-28 1988-08-01 Takeda Chem Ind Ltd 肝疾患治療剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
O'NEIL J.M. ET AL.: "The Merck Index", 2001, MERCK & CO., INC., article "Vitamin K", pages: 1787, XP002970487 *
WU FELICIA Y.H., LIAO WEI CHEN, CHANG HUI MIN: "Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays", LIFE SCIENCES, vol. 52, no. 22, 1993, pages 1797 - 1804, XP002970486 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065671A1 (fr) * 2004-01-06 2005-07-21 Eisai Co., Ltd. Prophylactique servant a empecher l'apparition d'un cancer du foie, comprenant un compose quinone en tant qu'ingredient actif
WO2005077351A1 (fr) * 2004-02-12 2005-08-25 Eisai Co., Ltd Remèdes de type quinones pour des maladies pulmonaires
WO2007091557A1 (fr) * 2006-02-10 2007-08-16 National University Corporation Nagoya University Préparation pharmaceutique pour le traitement ou la prévention du cancer du foie

Also Published As

Publication number Publication date
AU2003277184B2 (en) 2007-11-01
CA2488880A1 (fr) 2003-12-24
BR0311781A (pt) 2005-04-12
AU2003277184A1 (en) 2003-12-31

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