WO2013026373A1 - Utilisation de berbamine pour traiter la leucémie myéloïde chronique - Google Patents

Utilisation de berbamine pour traiter la leucémie myéloïde chronique Download PDF

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Publication number
WO2013026373A1
WO2013026373A1 PCT/CN2012/080297 CN2012080297W WO2013026373A1 WO 2013026373 A1 WO2013026373 A1 WO 2013026373A1 CN 2012080297 W CN2012080297 W CN 2012080297W WO 2013026373 A1 WO2013026373 A1 WO 2013026373A1
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day
dose
pharmaceutically acceptable
acceptable salt
berbamine
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PCT/CN2012/080297
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English (en)
Chinese (zh)
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徐荣臻
谢福文
赖洪喜
荣风光
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杭州本生药业有限公司
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Publication of WO2013026373A1 publication Critical patent/WO2013026373A1/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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the treatment of chronic myeloid leukemia, and in particular to the use of berberine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic myeloid leukemia.
  • CML chronic myeloid leukemia
  • Bcr Philadelphia chromosome
  • Imatinib is a Bcr-Abl tyrosine kinase inhibitor (TKI).
  • TKI Bcr-Abl tyrosine kinase inhibitor
  • Imatinib can interfere with both the signaling pathways of tumor cell growth and specific abnormal chromosomes, such as the characteristic Bcr-AbL in CML.
  • TKI first-generation tyrosine kinase inhibitor
  • IRIS study confirmed that imatinib 400 mg/d has excellent efficacy as a first-line option for the initial CML chronic phase (CP): an 8-year overall survival (OS) rate of 85 is expected %, If only CML-related deaths are calculated, the 8-year OS rate can reach 93%.
  • EFS event-free survival
  • PFS progression-free survival
  • AP accelerated
  • BP quick period
  • CCR cytogenetic response
  • MMR primary molecular response
  • TKI Abl tyrosine kinase inhibitor
  • IM imatinib
  • guanamine is a structurally unique bisbenzylisoquinoline isolated from the traditional Chinese medicine Bigber ⁇ (Berberis is is).
  • the use of small guanamine drugs approved for clinical use is mainly used to raise white blood cells, as an auxiliary drug for anti-tumor therapy, rather than a direct anti-tumor drug.
  • the clinical dose is 120 mg/time, 3 times a day, orally (2 mg/kg based on 60 kg body weight).
  • the inventors have found that high doses of berbamine are capable of killing leukemia stem cells and killing imatinib-resistant leukemia stem cells.
  • the present invention relates to the use of berbamine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of leukemia at a dose of from 5 mg/kg/day to 200 mg/kg/day.
  • the leukemia is chronic myeloid leukemia.
  • the dosage is from 20 mg/kg/day to 80 mg/kg/day.
  • the dosage is from 30 mg/kg/day to 60 mg/kg/day.
  • the dosage is from 40 mg/kg/day to 50 mg/kg/day.
  • the medicament is formulated for oral administration.
  • the invention relates to the use of Berberine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of imatinib-resistant chronic myeloid leukemia.
  • the medicament is administered at a dose of from 30 mg/kg/day to 100 mg/kg/day.
  • the medicament is administered at a dose of from 36 mg/kg/day to 90 mg/kg/day.
  • the medicament is administered at a dose of from 45 mg/kg/day to 60 mg/kg/day.
  • the medicament may be formulated for oral administration.
  • the present invention relates to a daily dosage independent unit for treating leukemia, comprising a small guanamine or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition in an amount sufficient to provide a body weight of 5 per kg patient A daily dose of 200 mg.
  • the amount of the small guanamine or a pharmaceutically acceptable salt thereof is sufficient to provide a daily dose of from 20 to 80 mg per kg of patient body weight.
  • the berbamine or its The amount of the pharmaceutically acceptable salt is sufficient to provide a daily dose of 30 - 60 mg per kg of patient body weight. In a further embodiment of the daily dosage unit of the invention, the amount of the small amide or a pharmaceutically acceptable salt thereof is sufficient to provide a daily dose of 40 to 50 mg per kg of patient body weight.
  • the daily dose independent unit is for the treatment of imatinib-resistant chronic myeloid leukemia.
  • the amount of the small amide or a pharmaceutically acceptable salt thereof is sufficient to provide a daily dose of from 30 to 100 mg per kg of patient body weight.
  • the amount of the small amide or a pharmaceutically acceptable salt thereof is sufficient to provide a daily dose of from 36 to 90 mg per kg of patient body weight.
  • the amount of the small amide or a pharmaceutically acceptable salt thereof is sufficient to provide a daily dose of 45 to 60 mg per kg of patient body weight.
  • the daily dose-independent unit contains one or more pharmaceutical tablets of berbamine or a pharmaceutically acceptable salt thereof.
  • the individual units are separate packages or separate sub-packages.
  • the invention in a fourth aspect, relates to a method of treating leukemia in a patient comprising administering to said patient d, guanamine or a pharmaceutically acceptable salt thereof at a dose of from 5 mg/kg/day to 200 mg/kg/day.
  • the leukemia is chronic myeloid leukemia.
  • the dosage is from 20 mg/kg/day to 80 mg/kg/day.
  • the dosage is from 30 mg/kg/day to 60 mg/kg/day.
  • the dosage is from 40 mg/kg/day to 50 mg/kg/day. In one embodiment of the method of the invention, the administration is oral.
  • the present invention relates to a method of treating imatinib-resistant chronic myeloid leukemia in a patient comprising administering to the patient berberine or a pharmaceutically acceptable salt thereof.
  • the dose administered is from 30 mg/kg/day to 100 mg/kg/day.
  • the dose administered is from 36 mg/kg/day to 90 mg/kg/day.
  • the dose administered is from 45 mg/kg/day to 60 mg/kg/day.
  • the administration is oral.
  • the present invention relates to berbamine or a pharmaceutically acceptable salt thereof for use in a method of treating leukemia in a patient, the method comprising administering a dose of from 5 mg/kg/day to 200 mg/kg/day
  • the patient is a guanamine or a pharmaceutically acceptable salt thereof.
  • the leukemia is 'ft myeloid leukemia.
  • the dosage is from 20 mg/kg/day to 80 mg/kg/day.
  • the dosage is from 30 mg/kg/day to 60 mg/kg/day.
  • the dosage is from 40 mg/kg/day to 50 mg/kg/day.
  • the administration is oral.
  • the present invention relates to a small indamine or a pharmaceutically acceptable salt thereof for use in a method of treating imatinib-resistant chronic myeloid leukemia in a patient, the method comprising administering
  • the patient is a guanamine or a pharmaceutically acceptable salt thereof.
  • the dose is from 30 mg/kg/day to 100 mg/kg/day.
  • the dose is from 36 mg/kg/day to 90 mg/kg/day.
  • the dosage is from 45 mg/kg/day to 60 mg/kg/day. In one embodiment of the berbamine or a pharmaceutically acceptable salt thereof of the present invention, the administration is oral.
  • Figure 1 shows the in vivo anti-leukemia activity of a single dose of berbamine.
  • A Effect of BBM on established CML xenograft growth.
  • B Effect of BBM on the body weight of tumor-bearing mice.
  • Figure 2 shows the pathological observation of CML xenografts.
  • A Excised typical CML xenografts of tumor-bearing mice and control untreated mice 45 days after oral BBM (150 mg/kg; 10 days per day).
  • B Effect of BBM on tumor structure and cell proliferation, tumors were excised and sectioned from BBM-treated and untreated mice. Tissues were stained with H&E to detect histomorphology or immunostained with anti-Ki-67 antibody to detect cell proliferation.
  • FIG. 1 shows the in vivo antitumor activity of the third dose regimen.
  • A Effect of the tri-dosing regimen on established CML xenograft growth.
  • ⁇ The effect of ⁇ on the body weight of tumor-bearing mice.
  • Figure 4 shows the in vivo antitumor activity of the sputum-dose regimen against sputum-resistant CML.
  • ⁇ The effect of ⁇ on the growth of established ⁇ -resistant CML xenografts.
  • FIG 5 shows the in vivo antitumor activity of the third dose regimen.
  • A ⁇ confrontation-resistant CML The effect of xenograft growth.
  • B Effect of IM on the body weight of tumor-bearing mice. detailed description
  • the 100 mg/kg sputum dose of the melamine treatment regimen achieved a therapeutic effect of 70% (14/20) of the remission of chronic myeloid leukemia xenografts within 10 days.
  • the 300 mg/kg berberine treatment regimen achieved a therapeutic effect of 83% (5/6) of imatinib-resistant chronic myeloid leukemia xenograft regression within 10 days.
  • Berylamine can be purchased on the market.
  • the term "pharmaceutically acceptable salts of the compounds of formula (I)” is exemplified by the formation of pharmaceutically acceptable anions (eg, sulfonate, mesylate, malate, acetate, citrate). , malonate, tartarate, succinate, benzoate, resistance
  • An organic acid addition salt formed from an organic acid of blood acidate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts can also be formed, including but not limited to hydrochlorides, sulfates, nitrates, bicarbonates and carbonates, phosphates, hydrobromides, hydroxamates, and the like.
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
  • polymorph refers to the solid crystalline form of a compound of the invention or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectral properties. Different physical properties include, but are not limited to, stability (e.g., to heat or light), compressibility and density (important for formulation and product production), and dissolution rate (which can affect bioavailability).
  • Differences in stability can result in chemical reactivity (eg, differential oxidation, such that when formulated from one polymorph, fades faster than when formed from another polymorph) or mechanical properties (eg, as storage) Changes in the kinetically favorable polymorphic tablet granules converted to thermodynamically more stable polymorphs) or both (for example, tablets of one polymorph are more susceptible to breakage at high humidity) .
  • the different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than the other or may be more difficult to filter or wash away from the shield due to, for example, differences in the shape or size distribution of its particles.
  • hydrate refers to a compound of the invention or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the guanamine of the compound of the present invention has the stereochemistry shown by the structural formula of Formula I.
  • the definitions and conventions of stereochemistry used herein generally follow MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (SP Parker, Ed,, McGraw-Hill Book Company, New York, 1984); and ELIEL, E. and WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, Inc., New York, 1994).
  • the invention also provides a pharmaceutical composition comprising a compound of formula I of the invention.
  • the invention provides a pharmaceutical composition comprising at least one of the compounds of formula I of the invention as described above, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical preparation of the present invention is produced by a known method, including a conventional mixing, dissolving or lyophilizing method.
  • the compounds of the invention may be formulated into pharmaceutical compositions and administered to the patient in a variety of ways suitable for the chosen mode of administration, e.g., orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
  • the compounds of the invention may be administered systemically, e.g., sputum, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Form use.
  • Such compositions and preparations should contain at least 1% of active compound.
  • the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
  • the amount of active compound is such that an effective dosage level can be obtained.
  • Tablets, lozenges, pills, capsules, and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch , potato starch, alginic acid, etc.; a lubricant such as stearic acid; and a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as mint, wintergreen or cherry.
  • a binder such as tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrant such as corn starch , potato starch, alginic acid, etc.
  • a lubricant such as stearic acid
  • a sweetener such as sucrose, fructose, lactose or aspartame
  • a flavoring agent such as mint, winter
  • any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound can be incorporated into sustained release formulations and sustained release devices.
  • the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
  • An aqueous solution of the active compound or a salt thereof may be prepared, optionally mixed with a non-toxic surfactant.
  • Dispersants in glycerin, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent microbial growth.
  • the pharmaceutical dosage form suitable for injection or infusion may comprise a sterile aqueous solution or dispersion of the active ingredient (optionally encapsulated in a liposome) comprising a ready-to-use preparation suitable for sterile injectable or infusible solutions or dispersions. Or sterile powder.
  • the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
  • the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, non-toxic glycerides, and suitable mixtures thereof.
  • Appropriate fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of dispersing agents, or by the use of surfactants.
  • Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).
  • isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay the absorbent (e.g., aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients listed above, followed by filter sterilization.
  • a sterile powder for the preparation of a sterile injectable solution, the preferred method of preparation is vacuum drying and Freeze-drying techniques which produce a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution.
  • Useful solid carriers include powdered solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
  • Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
  • Adjuvants such as fragrances
  • additional antimicrobial agents can be added to optimize the properties for a given use.
  • Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments. , soap, etc., used directly on the user's skin.
  • unit dosage form is a unit dispersion unit containing a unit dosage unit suitable for administration to humans and other mammalian bodies.
  • the unit dosage form can be a capsule or tablet, or a lot of capsules or tablets.
  • the pharmaceutical preparation of the present invention may also be prepared in the form of a daily dosage unit, which may be in the form of a separate package of individual daily dosage units, or may be a single package comprising a plurality of daily dosage units, for example, A plurality of daily dose independent units for one session or a plurality of daily dose independent units for multiple courses are included.
  • a single package may include 1 to 10 daily dose independent units, 1 20 daily dose independent units, 1, 30 daily dose independent units, 1 - 40 daily dose independent units, 1 - 50 daily doses Independent unit or more daily dose independent units, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 , 30, 35, 40, 45, 50 or more daily dose independent units.
  • the daily dosage unit may be formulated as a single dose, such as a tablet for single oral administration, a buccal tablet, a tablet, a capsule, an elixir, a suspension, a syrup, a wafer, etc. Form, or in the form of an injection solution or suspension for a single injection or infusion.
  • the daily dose independent unit may also be formulated in a multi-dose form, such as being divided into corresponding multi-dose according to the number of times of daily administration. For example, it may be in the form of 2-6 doses, 2-5 dose forms, 2-4 dose forms, 2-3 dose forms, 3-5 dose forms or 3-4 dose forms.
  • Each of the multiple dose forms of a single daily dose of discrete units may be equal or unequal, for example, one or more of the multiple doses may be higher than the other dose or doses, or multiple doses of a single daily dose of separate units
  • Each dose in the form may be incrementally increasing or decreasing.
  • RT-PCR analysis revealed a significant increase in CaMKIIy transcripts in CML tumor cells at the time of primitive cell crisis compared to normal hematopoietic cells.
  • CaMKIIyl protein is also present in the cross-immunoprecipitated complex using the GSK3p antibody.
  • the substrate phosphorylation motif of CaMKII gamma and the sequence of Ser21/9 comprising GSK-3 ⁇ / ⁇ and the substrate of CaMKII ⁇ that have been shown to phosphorylate GSK-3ct/p in Ser21/9
  • the acidification motif is identical to the sequence of Ser21/9 comprising GSK-3a/p.
  • CaMKIIy is a target for the anti-leukemia activity of the natural Chinese medicine product BBM.
  • CaMKiry may be a novel leukemia stem cell-specific marker and a CaMKII y /GSK-3/p-catenin that regulates CML LSC survival and self-renewal signaling pathways and CaMK] ⁇ /STAT3 signaling pathways The important molecular switch.
  • Confirmation of CaMKIIy kinase as a target for BBM illustrates the reason for the strong anti-LSC activity of berbamine.
  • targeting CaMKII gamma kinase may be a new strategy for the treatment of chronic myeloid leukemia.
  • the rat was purchased from the Shanghai Animal Center of the Chinese Academy of Sciences.
  • Berberine hydrochloride was purchased from Chengdu Xiaolong Natural Pharmaceutical Life Technology Co., Ltd.
  • K562 cells From the Institute of Cancer Research, Zhejiang University.
  • mice Seven-week-old rats were subcutaneously inoculated with human chronic myeloid leukemia cell K562 at a dose of 5 X 10 7 cells per mouse. After 24 hours, they were randomly divided into groups of 21 each. Medication group: The berbamine group was administered orally, at a dose of 100 mg per kilogram of body weight, once a day (administered). Control group: Replace with saline for 10 days. A total of 30 days were observed, during which the tumor weight, body weight, activity and diet were measured. At the end of the experiment, the mice were sacrificed and tumor tissues were taken and the actual weight was measured.
  • Tumor weight (: gram) ⁇ J, mouse weight (g) Mouse number control group, berbamine group, control group, berbamine group
  • the rat was purchased from the Shanghai Animal Center of the Chinese Academy of Sciences.
  • Berberine hydrochloride was purchased from Chengdu Xiaolong Natural Pharmaceutical Life Technology Co., Ltd.
  • Imatinib purchased from Swiss Novartis Pharmaceutical Co., Ltd.
  • Imatinib resistance and resistance K562 cells from the Institute of Cancer Research, Zhejiang University (both chronic myeloid leukemia cells)
  • mice Seven-week-old rats were subcutaneously inoculated with human chronic myeloid leukemia cell K562 at a dose of 5 X 10 7 cells per mouse. After 24 hours, randomized groups, 7 in the control group, 6 in the berbamine group, and 7 in the imatinib group. Medication group: The citrate group and the imatinib group were administered orally, at a dose of lOOmg per kilogram of body weight, 3 times a day (glycated ⁇ control group: replaced with normal saline, used for 10 days. A total of 45 days of observation) During the experiment, the weight, body weight, activity and diet of the rats were measured. At the end of the experiment, the mice were sacrificed, the tumor tissues were taken, and the actual weight was measured.
  • the survival rate of the control group was 28.6% (2/7), the tumor-free rate was 0% (0/7); the survival rate of the berbamine group was 100% (6/6), and the tumor-free rate was 83.3%. (5/6); The survival rate of the imatinib group was 100% (7/7), and the tumor-free rate was 42.9% (3/7).
  • the same three-dose regimen of imatinib did not cause regression.
  • the tumor weights of the control and IM treatment groups were 2.44 ⁇ 0.25 g and 1.02 ⁇ 1.23 g, respectively (Fig. 5A).
  • the body weights of the IM and treated groups were 13.0 ⁇ 0.25 g and 15.00 ⁇ 3.78 g, respectively (Fig. 5B).
  • the rat was purchased from the Shanghai Animal Center of the Chinese Academy of Sciences.
  • Berberine hydrochloride was purchased from Chengdu Xiaolong Natural Pharmaceutical Life Technology Co., Ltd.
  • Berbamine citrate was prepared by mixing citric acid and berbamine at a weight of 1:2.
  • K562 cells (from Zhejiang University Cancer Institute)
  • mice Seven-week-old rats were subcutaneously inoculated with human chronic myeloid leukemia cells K562 5 X 107 per mouse. After 24 hours, randomize.
  • the drug group The berbamine hydrochloride and the citrate citrate group were administered orally, at a dose of lOOmg per kilogram of body weight, 3 times a day (stomach).
  • Control group Replace with saline for 10 days. A total of 30 days were observed, during which the tumor weight, body weight, activity and diet were measured. At the end of the experiment, the mice were sacrificed and tumor tissue was taken and the actual weight was measured.
  • Table 3 different small guanamine salts 3 times a day, 100mg/kg each time, combined with 10 days of treatment program anti-leukemia effect comparison weight (g) tumor weight (: g)

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Abstract

L'invention concerne les utilisations de la berbamine ou d'un sel pharmaceutiquement acceptable de celle-ci en tant que composition pharmaceutique pour traiter la leucémie myéloïde chronique, en particulier la leucémie myéloïde chronique tolérante à l'imatinib.
PCT/CN2012/080297 2011-08-19 2012-08-17 Utilisation de berbamine pour traiter la leucémie myéloïde chronique WO2013026373A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0931544A2 (fr) * 1997-12-22 1999-07-28 Kaken Shoyaku Co., Ltd. Inhibiteur de l'activité NF-kB
CN1810247A (zh) * 2005-01-28 2006-08-02 中国医学科学院血液学研究所 小檗胺衍生物ebb在抑制人体肿瘤细胞侵袭转移的药物应用
CN1911277A (zh) * 2006-09-01 2007-02-14 高熠 治疗白细胞减少症的药物
CN101273989A (zh) * 2008-04-09 2008-10-01 浙江大学 一类小檗胺衍生物及其盐的应用
CN101429201A (zh) * 2008-12-22 2009-05-13 浙江大学 柠檬酸小檗胺盐及制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0931544A2 (fr) * 1997-12-22 1999-07-28 Kaken Shoyaku Co., Ltd. Inhibiteur de l'activité NF-kB
CN1810247A (zh) * 2005-01-28 2006-08-02 中国医学科学院血液学研究所 小檗胺衍生物ebb在抑制人体肿瘤细胞侵袭转移的药物应用
CN1911277A (zh) * 2006-09-01 2007-02-14 高熠 治疗白细胞减少症的药物
CN101273989A (zh) * 2008-04-09 2008-10-01 浙江大学 一类小檗胺衍生物及其盐的应用
CN101429201A (zh) * 2008-12-22 2009-05-13 浙江大学 柠檬酸小檗胺盐及制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUN, JIANRONG ET AL.: "The mechanism of apoptosis of chronic myeloid leukemia cells induced by the novel p210 bcr/abl inhibitor berbamine", NATIONAL MEDICAL JOURNAL OF CHINA, vol. 86, no. 32, 29 August 2006 (2006-08-29), pages 2246 - 2251 *

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