WO2014068972A1 - Agent utilisé pour réduire les effets secondaires du sorafénib - Google Patents

Agent utilisé pour réduire les effets secondaires du sorafénib Download PDF

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WO2014068972A1
WO2014068972A1 PCT/JP2013/006424 JP2013006424W WO2014068972A1 WO 2014068972 A1 WO2014068972 A1 WO 2014068972A1 JP 2013006424 W JP2013006424 W JP 2013006424W WO 2014068972 A1 WO2014068972 A1 WO 2014068972A1
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sorafenib
acceptable salt
bleeding
cdaa
deferasirox
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PCT/JP2013/006424
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English (en)
Japanese (ja)
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功 坂井田
山本　直樹
隆弘 山崎
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国立大学法人山口大学
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Priority to JP2014544316A priority Critical patent/JP6179904B2/ja
Publication of WO2014068972A1 publication Critical patent/WO2014068972A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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 4- [4- [3- [4-chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide (hereinafter also referred to as “sorafenib”).
  • agents for enhancing anticancer action by sorafenib for more details on side effect reducing agents, agents for enhancing anticancer action by sorafenib, and the like, more specifically, 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl ]
  • Side effects caused by administration of sorafenib or pharmacologically acceptable salt thereof in the treatment of cancer comprising benzoic acid (hereinafter also referred to as “deferacilox”) or a pharmacologically acceptable salt thereof as an active ingredient
  • the top cause of death in Japan is cancer, and countermeasures are the most important from the viewpoint of the health of the people.
  • Current cancer treatment methods include surgical treatment, radiotherapy, chemotherapy, immunotherapy, etc.
  • chemotherapy using an anticancer agent is widely used.
  • many anti-cancer drugs have the problem of many side effects because they damage not only cancer cells but also normal cells, and the development of effective therapeutic agents that can effectively treat cancer It is not easy, and sufficient therapeutic agents are not yet obtained.
  • Hepatocellular carcinoma is one of the most frequent solid cancers in the world, and the death rate from hepatocellular carcinoma in Japan in 2011 was the fourth highest death rate due to malignant neoplasm ( About 35,000 people a year).
  • Hepatocellular carcinoma is a cancer that recurs at an annual rate of 15 to 20% even if it is detected at an early stage. Eventually, fibrosis progresses and the number and size of the cancers increase, and the cells progress to advanced hepatocytes. Treatment becomes difficult.
  • anticancer drugs are injected directly into the liver from the arteries (hepatic arterial infusion chemotherapy) or ingestion. There is currently no effective treatment for advanced hepatocellular carcinoma that does not respond to these treatments.
  • Sorafenib one of the anticancer drugs, is a molecularly-targeted drug that can be administered orally. It directly inhibits Raf activity in the MAP kinase pathway that acts on cancer cell proliferation and acts on angiogenesis. It is a kinase inhibitor that simultaneously inhibits VEGF receptor and PDGF receptor activities.
  • This sorafenib was developed by Bayer Yakuhin and Onyx Pharmaceuticals, Inc., and sorafenib tosyl salt (BAY43-9006) was formulated. As of September 2009, hepatocellular Approved in over 70 countries for cancer. In Japan, it is marketed by Bayer Yakuhin as Nexavar® and is the only approved treatment for systemic chemotherapy for unresectable hepatocellular carcinoma.
  • sorafenib or pharmacologically acceptable salt thereof hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding
  • dermatitis eczema
  • erythema gastrointestinal bleeding
  • respiratory tract bleeding cerebral bleeding
  • oral bleeding nasal bleeding
  • nail bed bleeding causes serious side effects such as hematoma, tumor bleeding, loss of appetite, weight loss, liver weight, and liver function, not only significantly lowering the patient's quality of life but also decreasing early after the start of medication Cases where drugs or withdrawal are often a problem.
  • Non-Patent Document 2 it is known that deferasirox alone, which is an iron chelator, suppresses liver fibrosis and liver cancer (see, for example, Non-Patent Document 2), but the liver fibrosis and liver cancer. The generation suppressing effect was not sufficient.
  • diseases associated with the growth and / or proliferation of neoplastic cells and / or tissues in mammals, especially humans, and / or triggered by refractory angiogenesis are: (a) iron chelators; and (b) one species
  • a method for preventing or treating with a combination of medicines containing the above pharmaceutically active agents is known (see, for example, Patent Document 2).
  • this method only shows anti-proliferative activity at the cellular level in combination with deferasirox and 5-fluorouracil, mitomycin C, cisplatin, leucovorin and Tumdex.
  • An object of the present invention is to reduce an adverse effect in cancer treatment by administering sorafenib or a pharmacologically acceptable salt thereof, or an anticancer effect by administering sorafenib or a pharmacologically acceptable salt thereof. It is to provide an enhancer.
  • the present inventors have intensively studied, and in studying a concomitant drug with sorafenib or a pharmacologically acceptable salt thereof, the action mechanism of the therapeutic effect on cancer of the iron chelator itself.
  • Sorafenib or its pharmacologically acceptable salt was used in combination with an iron chelator, it was accidentally found that sorafenib tosylate and iron chelator deferasirox
  • the improvement of hand-foot syndrome which is one of the side effects of sorafenib, was observed.
  • the present invention relates to [1] 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof.
  • An agent for reducing side effects caused by administration of an acceptable salt [2] a side effect reducing agent according to [1] above, wherein the cancer treatment is treatment of hepatocellular carcinoma, and [3] side effects But hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding, hematoma, tumor bleeding, loss of appetite, weight loss, liver weight reduction, That one of the liver function decline
  • side effects such as skin symptoms, bleeding, decrease in body weight and liver weight, and decrease in survival time due to administration of sorafenib or a pharmacologically acceptable salt thereof can be improved.
  • the enhancer of anticancer action of the present invention by enhancing the carcinogenesis inhibitory effect of hepatocellular carcinoma or the fibrosis inhibitory effect of liver tissue by administration of sorafenib or a pharmacologically acceptable salt thereof, Cancer treatment is possible by administration of a smaller amount of sorafenib or a pharmacologically acceptable salt thereof than before, and it is possible to administer sorafenib or a pharmacologically acceptable salt thereof in an early and long-term manner. Therefore, it becomes possible to suppress hepatic fibrosis of refractory cirrhosis and suppress the development of hepatocellular carcinoma.
  • FIG. 2 It is a figure which shows the result of having investigated the survival rate of the liver fibrosis / liver carcinogenesis rat.
  • the vertical axis represents the survival rate of rats when all the rats are alive in each group, and the horizontal axis represents the number of days (days) from the start of administration of choline-deficient diet (CDAA diet).
  • CDAA diet choline-deficient diet
  • FIG. 2 The upper left of FIG. 2 is (1) CDAA only continuous administration group (CDAA only 16w), the upper part of FIG. 2 is (2) CDAA + deferasirox single agent continuous administration group (CDAA + Deferairox 16w), and the upper right of FIG.
  • CDAA + sorafenib + deferasirox combination continuous administration group CDAA + Sorafenib + Deferairox 16w.
  • the vertical axis is Azan positive area (%), and the horizontal axis is from the left (1) CDAA only continuous administration group (CDAA16w), (2) CDAA + deferasirox single agent continuous administration group (CDAA + DEF 16w) (3) CDAA + sorafenib single agent continuous administration group (CDAA + SOR 16w), (4) CDAA + sorafenib + deferasirox combination continuous administration group (CDAA + SOR + DEF 16w).
  • the vertical axis is the tumor area (%) by GST-P staining
  • the horizontal axis is from the left (1) CDAA only continuous administration group (CDAA16w), (2) CDAA + deferasirox single agent continuous administration group (CDAA + DEF 16w), (3) CDAA + sorafenib single agent continuous administration group (CDAA + SOR 16w), (4) CDAA + sorafenib + deferasirox combination continuous administration group (CDAA + SOR + DEF 16w).
  • the vertical axis is the number of tumors per unit area (1 cm 2 )
  • the horizontal axis is the same as in the upper part of FIG.
  • the side effect reducing agent of the present invention As an agent for reducing side effects caused by administration of sorafenib or a pharmacologically acceptable salt thereof produced in the cancer treatment of the present invention (hereinafter also simply referred to as “the side effect reducing agent of the present invention”), the following formula (I): 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid (deferasirox) or a pharmaceutically acceptable salt thereof represented by the formula: If it contains as an active ingredient, it will not restrict
  • the compound represented by the above formula (I) is sold as a chelating agent from Novartis Pharma Co., Ltd. as “XJADE (registered trademark)” in Japan and as “Exjade (registered trademark)” overseas.
  • XJADE registered trademark
  • Exjade registered trademark
  • a commercially available product may be used, or a known product described in, for example, International Publication No. 97/49395 published on Dec. 31, 1997. It can be manufactured by a method.
  • Examples of pharmacologically acceptable salts of deferasirox include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and transition metal salts such as zinc salts.
  • Hydroxy-lower alkylamines such as cyclic amine salts, mono-, di- or tri-lower alkylamine salts, mono-, di- or trihydroxy-lower alkylamine salts, polyhydroxy-lower alkylamine salts, etc. And salts thereof and hydroxy-lower alkyl-lower alkylamine salts.
  • Sorafenib is a multikinase inhibitor that inhibits Raf kinase, PDGFR kinase, VEGFR kinase, and KIT kinase.
  • the compound represented by the above formula (II) is sold by Bayer Yakuhin as “Nexavar (registered trademark)” in Japan and “Nexavar (registered trademark)” overseas.
  • This sorafenib or a pharmacologically acceptable salt thereof may be a commercially available product, or can be produced by a known method described in, for example, Japanese Patent No. 3845792.
  • sorafenib examples include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and other inorganic acid salts, acetates, trifluoroacetic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, butyrate, valerate, citrate, fumarate, maleate, malate, p-toluenesulfonic acid (tosyl) Acid) salts, methane sulfonates, trifluoromethane sulfonates, benzene sulfonates, 1-naphthalene sulfonates, 2-naphthalene sulfonates, and the like. Can be preferably mentioned.
  • side effects are not particularly limited as long as they are caused by administration of sorafenib or a pharmacologically acceptable salt thereof, but skin symptoms (hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema), bleeding ( Gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding, hematoma, tumor bleeding), loss of appetite, weight loss, liver weight reduction, liver function decline, oxidative stress, especially limb syndrome
  • Preferable examples include, exfoliative dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, loss of appetite, weight loss, and liver weight reduction.
  • the reduction of side effects means that the symptoms of the above side effects such as skin symptoms, bleeding, loss of appetite, etc. are reduced. For example, if the symptoms are skin symptoms, the area where the symptoms occur is reduced, or if bleeding This means that the bleeding site and the amount of bleeding decrease. Furthermore, as a result of increased side effects caused by excessive administration of sorafenib or a pharmacologically acceptable salt thereof, the survival rate within a predetermined period may be reduced. However, the increase of such side effects can also be improved.
  • the anticancer activity enhancer (hereinafter also referred to as “the anticancer activity enhancer of the present invention”) by sorafenib or a pharmaceutically acceptable salt thereof of the present invention is represented by the above formula (I).
  • the anticancer activity enhancer of the present invention contains deferasirox or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmacologically acceptable salt of deferasirox or sorafenib or the pharmacologically acceptable salt thereof in the anticancer activity enhancer of the present invention the same as the case of the side effect reducing agent of the present invention described above. Mention may be made of salts.
  • the cancer to be the subject of the present invention is not particularly limited as long as sorafenib or a pharmacologically acceptable salt thereof exhibits an anti-cancer effect.
  • sorafenib or a pharmacologically acceptable salt thereof exhibits an anti-cancer effect.
  • hepatocellular carcinoma, renal cell carcinoma, Breast cancer can be mentioned, and hepatocellular carcinoma can be mentioned more suitably.
  • the anti-cancer effect of the anti-cancer effect enhancer of the present invention is not particularly limited, but it suppresses carcinogenesis such as hepatocellular carcinoma, suppresses fibrosis of liver tissue, suppresses oxidative stress, and improves the function of organs such as liver. Suitable examples include suppression of hepatocellular carcinoma carcinogenesis or suppression of liver tissue fibrosis.
  • Deferasirox or a pharmacologically acceptable salt thereof in the side effect reducing agent of the present invention or the anticancer activity enhancing agent of the present invention reduces side effects caused by administration of sorafenib or a pharmacologically acceptable salt thereof.
  • the kit for the treatment or prevention of cancer of the present invention includes deferasirox or a pharmacologically acceptable salt thereof, and sorafenib or a pharmacologically acceptable salt thereof as individual active ingredients.
  • the kit is not particularly limited as long as it is a kit containing a combination of preparations (combination preparation), and may include a package insert or the like describing a method for treating or preventing cancer using the kit, and treating or preventing such cancer. Because the side effect of sorafenib is reduced and the anticancer effect is enhanced, long-lasting administration is possible from an early stage, which suppresses liver fibrosis of refractory cirrhosis, It becomes possible to suppress the onset of cell cancer.
  • Preferred examples of the administration target of the side effect reducing agent of the present invention, the anticancer agent enhancing agent of the present invention, and the kit for treating or preventing cancer of the present invention include mammals or mammalian cells.
  • mammals humans, mice, rats, guinea pigs, rabbits, birds, sheep, pigs, cows, horses, cats, dogs, monkeys, chimpanzees can be more preferably mentioned, and humans are particularly preferred.
  • each combination of the side effect reducing agent of the present invention (single preparation or mixed preparation), the anti-cancer activity enhancer of the present invention (single preparation or mixed preparation), and the kit for treating or preventing cancer of the present invention
  • the dosage form of the preparation include powders, granules, tablets, solutions, emulsions, suspensions, syrups, capsules, suppositories, injections and the like.
  • preparations are prepared according to the necessity of the preparation, as appropriate pharmacologically acceptable carriers such as solvents, excipients, binders, solubilizers, suspending agents, emulsifiers, tonicity agents, Manufactured by blending optional ingredients such as buffers, stabilizers, soothing agents, preservatives, antioxidants, colorants, lubricants, disintegrants, wetting agents, adsorbents, sweeteners, diluents, etc. be able to.
  • pharmacologically acceptable carriers such as solvents, excipients, binders, solubilizers, suspending agents, emulsifiers, tonicity agents.
  • optional ingredients such as buffers, stabilizers, soothing agents, preservatives, antioxidants, colorants, lubricants, disintegrants, wetting agents, adsorbents, sweeteners, diluents, etc. be able to.
  • the method for administering each component of the kit for reducing or reducing the side effect of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention comprises the effect of reducing the side effect of the present invention, although it is not particularly limited as long as it has an effect of enhancing the anticancer action of the invention, oral administration or parenteral administration such as rectal administration, buccal administration, subcutaneous administration, intramuscular administration, intravenous administration, etc. can be mentioned, Oral administration is preferred in that it does not require heavy continuous infusion treatment.
  • the dose of deferasirox in the kit for reducing side effects of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention includes the reduction of the side effects of the present invention.
  • it is not particularly limited as long as it has the effect of enhancing the anticancer action of the present invention, for example, in the case of a human adult, it is 20 to 500% by mass, preferably 50 to 300% by mass, more preferably to sorafenib.
  • a preferred example is 100 to 200% by mass, more preferably 130 to 170% by mass.
  • the daily dose of deferasirox can be appropriately adjusted according to the dose of sorafenib. For example, in the case of a human adult, 5 to 30 mg / kg, preferably 10 to 25 mg / kg, more preferably Can be 18 to 22 mg / kg.
  • the daily dose of sorafenib is not particularly limited.
  • the administration time zone of deferasirox in the kit for reducing side effects of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention is not particularly limited, even in the morning. Evening may be possible, but when the dose is large, it is preferable to administer it in multiple doses per day.
  • CDAA-only continuous administration group (2) CDAA + deferasirox 20 mg / kg / day single agent continuous administration group (hereinafter also referred to as “CDAA + deferasirox single agent continuous administration group”) (3) CDAA + sorafenib 13.3 mg / kg / day single agent continuous administration group (hereinafter also referred to as “CDAA + sorafenib single agent continuous administration group”) (4) CDAA + sorafenib 13.3 mg / kg / day + deferasirox 20 mg / kg / day combination continuous administration group (hereinafter also referred to as “CDAA + sorafenib + deferasirox combination continuous administration group”)
  • XJade registered trademark
  • Nexavar registered trademark
  • Bayer Yakuhin the sorafenib
  • Nexavar 1 mg contains 1 mg of sorafenib (1.37 mg as sorafenib tosylate). All the administration methods were oral administration, and in the above (4) CDAA + sorafenib + deferasirox combination continuous administration group, sorafenib and deferasirox were administered simultaneously.
  • the (3) CDAA + sorafenib single agent continuous administration group had a decrease of 32% (166.2 ⁇ 18.18) compared to the (1) CDAA alone continuous administration group (245.1 ⁇ 7.7 g). 8g), however, (4) CDAA + sorafenib + deferasirox combined continuous administration group (1) CDAA alone decreased only 10% compared to the continuous administration group (221.4 ⁇ 5.1 g).
  • the liver weight was reduced by 50% in the (3) CDAA + sorafenib single agent continuous administration group as compared with the (1) CDAA alone continuous administration group (14.7 ⁇ 0.8 g) (7.3).
  • the solid line (-) is (1) the CDAA-only continuous administration group, and (2) the CDAA + deferasirox single-drug continuous administration group.
  • liver function fibrosis inhibitory effect (Preparation of paraffin-embedded undyed specimen) Azan staining was performed on liver fibrosis / carcinogenesis rats of the 16th week (112 days) of the four groups (1) to (4) obtained in Example 1. A small amount of liver tissue was collected from each group of rats (1) to (4), the collected liver tissue was immersed in formalin, and a paraffin-embedded unstained sample was prepared from the formalin-fixed tissue.
  • Azan staining The above-mentioned paraffin-embedded unstained specimen was subjected to Azan staining for fiber tissue staining according to a conventional method. That is, after deparaffinization of the paraffin section, it was mordanted for 20 minutes in a mixed solution of 10% potassium dichromate / 10% trichloroacetic acid and washed with distilled water (5 minutes). It was immersed in an 8% orange G aqueous solution for 10 minutes. After washing with distilled water (about 10 seconds, the same applies hereinafter), the sample was immersed in azocarmine G solution for 60 minutes, washed with distilled water and then immersed in aniline / alcohol for 3 seconds for fractionation.
  • liver fibrosis was suppressed to some extent in the (1) CDAA-only continuous administration group (2) CDAA + deferasirox single-agent continuous administration group, but (4) In the continuous administration group of CDAA + sorafenib + deferasirox combination, liver fibrosis was suppressed to such an extent that hepatic fibrosis was hardly observed.
  • CDAA + sorafenib + deferasirox in the continuous administration group of CDAA + sorafenib + deferasirox combination, liver fibrosis was suppressed to such an extent that hepatic fibrosis was hardly observed.
  • the ratio (%) of the GST-P positive area per area of the tissue piece and the number of tumors per unit area (1 cm 2 ) were determined by a fluorescence microscope image processing system Meta Morph (manufactured by Olympus). The results are shown in FIG.
  • the tumor area is reduced by about 1/30 in (3) CDAA + sorafenib single agent continuous administration group compared with (1) CDAA only continuous administration group, but (2) CDAA + deferasirox single In the continuous administration group, only about 1 / 6.5 was decreased.
  • the tumor area is reduced to about 1/46 compared to the (1) CDAA alone continuous administration group. It was. From this result, it was clarified that the combined use of sorafenib and deferasirox enhances the liver fibrosis inhibitory effect of sorafenib as a synergistic effect as well as an additive effect.
  • the number of tumors decreased by about 1/7 in the (3) CDAA + sorafenib single agent continuous administration group compared to (1) the CDAA only continuous administration group.
  • the Rocks single-dose continuous administration group had decreased only about 1/3.
  • the number of tumors was surprisingly about 1/20 of that of the group administered with (1) CDAA alone. It had fallen to. From this result, it became clear that the combined use of deferasirox with sorafenib enhances the liver carcinogenesis-suppressing effect of sorafenib as a synergistic effect as well as an additive effect.
  • the side effect reducing agent of the present invention, the anticancer agent enhancing agent of the present invention, and the kit for treating or preventing cancer of the present invention can be advantageously used in the fields of medicine and medicine.

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Abstract

Le problème décrit par la présente invention est de fournir un agent permettant de réduire les effets secondaires d'un traitement du cancer basé sur l'administration de sorafénib ou d'un sel associé pharmaceutiquement acceptable, et d'un agent de potentialisation de l'activité anticancéreuse à partir de l'administration de sorafénib ou d'un sel associé pharmaceutiquement acceptable. Pour ce faire, sont ainsi préparés : un agent permettant de réduire les effets secondaires provoqués par l'administration de sorafénib ou d'un sel associé pharmaceutiquement acceptable pendant un traitement du cancer, l'agent réduisant les effets secondaires comprenant comme principes actifs le déférasirox ou un sel associé pharmaceutiquement acceptable ; et un agent de potentialisation de l'activité anticancéreuse à partir de l'administration de sorafénib ou d'un sel associé pharmaceutiquement acceptable, l'agent de potentialisation comprenant du déférasirox ou un sel associé pharmaceutiquement acceptable.
PCT/JP2013/006424 2012-11-05 2013-10-30 Agent utilisé pour réduire les effets secondaires du sorafénib WO2014068972A1 (fr)

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WO2019059246A1 (fr) * 2017-09-21 2019-03-28 味の素株式会社 Composition pour prévenir ou améliorer le syndrome main-pied
JP2020125346A (ja) * 2016-07-29 2020-08-20 チョン クン ダン ファーマシューティカル コーポレーション 血管破壊剤を含む肝臓癌治療用の組成物
CN112843052A (zh) * 2021-03-26 2021-05-28 湖南师范大学 新型表观遗传因子抑制剂2800z在制备抗肝癌药物增敏剂中的应用

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JP7001736B2 (ja) 2016-07-29 2022-01-20 チョン クン ダン ファーマシューティカル コーポレーション 血管破壊剤を含む肝臓癌治療用の組成物
JP7001736B6 (ja) 2016-07-29 2022-03-14 チョン クン ダン ファーマシューティカル コーポレーション 血管破壊剤を含む肝臓癌治療用の組成物
WO2019059246A1 (fr) * 2017-09-21 2019-03-28 味の素株式会社 Composition pour prévenir ou améliorer le syndrome main-pied
CN112843052A (zh) * 2021-03-26 2021-05-28 湖南师范大学 新型表观遗传因子抑制剂2800z在制备抗肝癌药物增敏剂中的应用

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