General

Scientific Names: Fructus Bruceae, Brucea amarissima Desv. Ex Gomes, B. sumatrana Roxb., Gonus amarissimus Lour.

Common Names: Ya DanZi , Lao Ya Dan, Ya Dan, Ku Shen Zi, Ku Zhen Zi, Xie Ku Lian, Xiao Ku Lian.

BOTANICAL

 

A shrub or small tree, 1–3 m high; younger parts softly pubescent. Leaves compound-paripinnate; leaflets 5–11, oval-lanceolate, 5–10 cm long by 2–4cm wide; apex acuminate, base broadly cuneate and often somewhat oblique; margin serrate; both surfaces densely pubescent, especially the underside. Flowers minute, purple, in numerous small cymes or clusters collected into axillary panicles. Sepals 4, connate at the base. Petals 4, villous, glandular at the tips. Male flowers, stamens 4, pistil reduced to a stigma; female flowers, stamens 4, much reduced. Ovary with 4 free carpels. Fruit and drupe ovoid, black when ripe. Seeds, compressed, rugose, blackish brown.

General Appearance: The fruit is ovoid, 6–10 mm long by 4–7mm in diameter. Externally black or brown, with raised reticulate wrinkles, the lumen irregularly polygonal, obviously ribbed at both sides. Apex acuminate, base having a dented fruit stalk scar, shell hard and brittle. Seeds ovoid, 5–6 mm long by 3–5mm in diameter, externally yellowish white, reticulate; t esta thin, cotyledons milky white and oily.

The ripe seed of Brucea javanica (L.) Merr., or Rhus chinensis, of the Anacardiaceae family. A decidious tree, and native to east Asia, the plant is grown in lowland, hills and mountains in China , Japan , Indochina , Java, Kelantan , Malaysia , Sumatra , and even the Himalayas .

The Java Brucea tree grows to 6 m high. It is in flower in August. The flowers are dioecious (individual flowers are either male or female, but only one sex is to be found on any one plant so both male and female plants must be grown if seed is required) and are pollinated by bees. It requires well-drained soil, and cannot grow in the shade.
In China , the plant is grown in such provinces or regions as Guangxi , Guangdong , etc. Reaped in autumn when the fruit ripens, the fruit is then dried in the sun, shelled, and the kernels taken for use.

 

Pharmacology

Quassinoid triterpenes, including bruceantin, bruceantinol, bruceantinoside A, bruceins A–G and Q, brucein E 2-O-Beta-D-glucoside, bruceolide, bruceosides A– C, brusatol, dehydrobruceantinol, dehydrobruceins A and B, dehydrobrusatol, dihydrobrucein A, yadanzigan, yadanziolides A–D, and yadanziosides A–P predominate as the secondary metabolite constituents.

The seed of Bruceae includes oil 56.23%, among which 1.36% are unsaponified; 92.7% are saponified, including oil acid 81.87%、linoleic acid 3.37%、stearic acid 2.65%、palm acid 6.62%; the seed includes various kinds of bitter elements that are similar to Quassin: Brusatol, Bruceine A, B, C, D, E, F, G, H. Besides, It also includes bruceoside A,B,C.

  • Yang Zheng Qi, et al. 1997, Chemical Studies of the Active antitumor Constituents from the Fruit of Brucea Javannica (L.) Merr (II).
  • Yang Zheng Qi, et al. 1996, Chemical studies of the active antitumor components from the fruits of brueca javanica (L.) merr.
  • Fukamiya N, et al, 1992, Antitumor agents, 127. Bruceoside C, a new cytotoxic quassinoid glucoside, and related compounds from brucea javanica.
  • Toyota T, et al, 1990, Antitumor agents, 118. The isolation and characterization of bruceanic acid A, its methyl ester, and the new bruceanic acids B, C, and D, from Brucea natidysenterica.
  • Fukamiya N, et al, 1987, Antitumor agents, 90. Bruceantinoside C, a new cytotoxic quassinoid glycoside from Brucea antidysenterica.
  • Sakaki T, et al, 1986, Yadanzioside P, a new antileukemic quassinoid glycoside from Brucea javanica (L.) Merr with the 3-0-(beta-D-glucopyranosyl) bruceantin structure.
  • Fukamiya N, et al, 1986, Antitumor agents, 79. Cytotoxic antileukemic alkaloids from Brucea antidysenterica.
  • Okano M, et al, 1981, Antitumor agents. 39. Bruceantinoside-A and –B, novel antileukemic quassinoid glucosides from Brucea antidysenterica.
  • Phillipson JD, Darwish FA, 1981, Bruceolides from Filjian Brucea javanica.
  • Phillipson JD, Darwish FA. 1979, TLX-5 lymphoma cells in rapid screening for cytotoxicity in Brucea extracts.
  • Kupchan SM, et al, 1973, Bruceantin, a new potent antileukemic simaroubolide from Brucea antidysenterica.
  •  

    Efficacy

    IN VITRO:

  • Cuendet M, Pezzuto JM. 2004, Antitumor activity of bruceantin: an old drug with new promise.
  • Mata-Greenwood E, et al. 2002, Brusatol-mediated induction of leukemic cell differentiation and G(1) arrest is associated with down-regulation of c-myc.
  • Liu Yue, et al.2001, Brucea Javanica Oil Emulsion Induces Apoptosis in Human Urinary Bladder Cancer Cell Line BIU-87 Cell.
  • Liu Yue, et al. 2001, Effect of Brucea Javanica on Cell of Human Bladder Neoplasms.
  • Tang Tao, et al, 2001, Reversal of multidrug resistance and inhibition of DNA topoisomerase II by emulsion of seed oil of Brucea Javanica.
  • Liu Yue, et al. 2001, An experimental study of brucea javanica oil emulsion on bladder carcinoma.
  • Li xiao gong, et al. 1998, An Experimental study of effect of brucea javanica oil emulsion on human renal cell carcinoma.
  • Ohnishi S, et al, 1995, Bruceosides D, E, and F, three new cytotoxic quassinoid glucosides from Brucea javanica.
  • Xuan YB, et al, 1994, Growth inhibition of the emulsion from to Brucea javanica cultured human carcinoma cells.
  • 1 . 对艾氏腹水癌、 Luis 肺癌及 S180 等体内外抑瘤试验中都显示其疗效.
    2 . 能提高机体的免疫能力;对肿瘤细胞有靶向性。

    IN VIVO:

    1.Wang He, et al. 2001, Effects of Brucea Javanica Oil Emulsion Intravesical Instillation for the Treatment of Bladder Carcinoma in Mice.

    2. 10% 鸦胆子油静脉乳抗肿瘤作用:

    小鼠体内抗癌作用: 1 ,对艾氏腹水癌的作用: 小鼠体重 20 ± 0.5g ,每组 10 只,接种艾氏腹水癌后次日给药。两个给药组分别腹腔注射鸦胆子静脉乳 2.5g/ ( kg. 天) × 7 天、 5.0g/ ( kg .天) × 7 天,并设对照组,停药后观察动物 45 天内生存天数,计算生命延长率。结果表明,两个剂量给药组平均生存天数均显著长于对照组( P 均 < 0.001 )。 2 , 对实体瘤 S37 、 S180 的作用:小白鼠体重 20 ± 0.5g ,右前肢腋部皮下接种癌细胞悬液,每组 10 只,接种次日起每天于肿瘤局部给药 2.5g/ ( kg. 天) × 7 天,给药后 15 天处死动物,记录体重,肿瘤重量,计算肿瘤抑制率。结果表明鸦胆子油静脉乳对小鼠实体瘤 S37 、 S180 均有一走的抗癌作用。

    体外抗癌作用: 用 1.25% 的鸦胆子静脉乳与艾氏腹水癌细胞体外配养1、3 小时,伊红染色法的赤染率都为 100% 。形态法实验结果鸦胆子静脉乳对癌细胞的损伤为膜变性、膜破裂和核固缩等,表明鸦胆子油静脉乳对艾氏腹水癌细胞肝癌腹水型癌细胞有直接损害作用。 经小鼠精原细胞法证明鸦胆子油静脉乳尚有抑制小鼠精原细胞有丝分裂的作用。

    鸦胆子油乳剂对艾氏腹水癌细胞的杀伤动力学效应:采用放射自显影方法观察中 10% 鸦胆子油乳剂对接种 7 天的艾氏腹水癌小鼠 S 期、 G2 期和 Go 期细胞的影响。 S 期杀伤结果表明,给药后 8 小时, S 期及非 S 期细胞损伤均呈高峰,但 S 期细胞的损伤百分率较非 S 期高。标记指数( LI )在 2 小时后明显下降, 24 小时时 LI 下降为 5.2% ,表明给药时处于 S 期的细胞大部分被药物破坏。 经3H 一 TdR 标记后,再用秋水仙酰胺阻断的实验表明,给药组标记分裂指数( PLM )上升幅度与对照组比较明显下降。由于药物处理时几乎未见损伤的 M 期细胞,并可见有丝分裂各期的细胞,所以经药物处理后 MI 无明显上升并非药物直接损伤 M 期细胞所致,说明鸦胆子油乳剂可以抑制或损伤 G2 期细胞,从而减少及延长 G2 期细胞进入 M 期。用连续标记方法确定 Go 期细胞为 47.8% ,给药后 5 小时, Go 期细胞损伤率为 17% ,说明鸦胆子油乳剂对 Go 期细胞亦有一定杀伤作用。 经放射自显影证实,鸦胆子油乳剂对 3H 一 TdR 参入 DNA 生物合成有明显的抑制作用,给药后 0.5 小时 , LI 为 11% , 24 小时 LI 为 33% ,表明药物对艾氏腹水癌细胞呈可逆性抑制。

    抗白血病作用:鸦胆子含苦木素类糖甙 Brnceoside A 、 B 、 Yadanziosides A-H 、 Yadanziosides F 、 I 、 J 、 L 、 P 显示有抗白血病活性。鸦胆子苦醇对 P-388 白血病显示有效的抗白血病作用(小鼠腹腔注射 0.125mg/kg/ 天, T/C=158), Cleomiscosin A 在体外对 P-388 淋巴性白血病有活性(半数有效量= 0.4 μ g/ml )。

    抗其它肿瘤作用:甲基胆蒽醋酮诱发的小鼠皮肤癌和乳头状瘤进行试验,证明鸦胆子仁糊剂和水剂局部应用,能使瘤细胞发生退行性变和坏死。但对正常组织亦有类似作用。鸦胆子苦醇在 0.5mg/kg 时,对小鼠 S180 瘤株有边缘活性。(Source

     

    CLINICAL:

  • Wei Bo, et al. 1999, Interventional Treatment of Advanced Hepatocellular Carcinoma with Brucea Javanica-Lipiodol “Sandwich” Embolizations and Intratumoral Injections of Ethanol and Immunocytokines. (Source)
  • Wang ZQ, 1992, Combined therapy of brain metastasis in lung cancer. (Source)
  • Su SY., 1985, Treatment of lung cancer with brain metastasis using an intravenous drip of a 10% emulsion of Brucea javanica seminal oil. (Source)
  • 在临床应用中所观察到的特点是:

    1 . 抗癌谱广,对肺癌、转性性脑瘤、肝癌、乳腺癌等均显示了一定的抗肿瘤作用,尤其在控制胸腹水方面显示出很 强的疗效.
    2 . 除静脉炎以外几乎没有任何全身性的毒副反应.
    3 . 能透过血脑屏障 [5] ,并能使颅 内压下降.
    4 . 治疗效果似乎与鸦乳药物用量有正相关作用。
    Sources)

    本品经中国医科大学附属第三医院胸外科,陕西中医学院附属医院肿瘤科,沈阳军区总医院,南京八一医院,中山医学院附属医院,大连铁路医院,北京市肿瘤防治研究所,上海第一医院附属中山医院肿瘤研究室等单位临床验证,结果证实:
    1 、用本品治疗消化系统肿瘤及其它肿瘤共 570 例,一疗程为一个月,治疗一至二个疗程以上,并观察一个月以上,显效(病灶缩小 50% 以上)占 4.35% ,稳定者(病灶缩小少于 50% ,增大不超过 25% )占 73.91% ,进展者(病灶增大 26% 以上)占 21.74% 。
    2 、病理组织学观察表明,鸦胆子油与化疗 5-Fu 一样,作用于肿瘤组织,使癌细胞核破碎,坏死,变性。免疫反应可见体液免疫反应明显增高,细胞免疫也有所增强。如治疗胃癌病人,肿块坏死灶增加,明显优于手术组 (P<0.05) 与化疗组持平;癌周免疫反应指标(癌周淋巴 - 浆细胞反应)阳性例数,明显优于手术组 (P<0.05), 与化疗组无明显差异。
    3 、临床症状普遍改善。表现为食欲增加、疼痛减缓、体重增加、创面结痂、肿块变软、局部淋巴手术粘连减轻,特别对因放化疗造成骨髓抑制和严重消化道反应致使中断治疗者,使用本品可使血象、肝功及细胞免疫功能不致下降,保证放化疗的顺利进行。
    4 、本品治疗胃癌、肺癌、直肠癌、食管癌、肝癌、肺癌脑转移。
    5 、使用本品 10 个疗程以上,未见严重毒副反应。
    总之,鸦胆子油口服乳液具有明显的抗癌作用,同时具有提高细胞免疫功能的特点,建议与其它化疗或放疗联合用药,抵消放化疗的副作用,达到协同治疗效果。 (Source)

    浙江省人民医院放疗科利用两年时间,应用鸦胆子油乳配合肝动脉栓塞化疗( TACE ,也称介入)治疗原发性肝癌,取得了较为满意的疗效。 研究人员观察了 66 例中晚期原发性肝癌患者,治疗组 34 例,给予鸦胆子油乳 30 毫升加入生理盐水 250 毫升中静脉滴注,每日 1 次, 30 天为 1 疗程,配合 TACE 治疗。对照组仅用 TACE 法,用药、剂量和间隔时间与治疗组相同。临床观察指标显示,治疗组 12 例乏力、纳差明显改善,睡眠恢复正常,体重增加,腹痛、腹胀消失; 15 例乏力、纳差改善,腹痛、腹胀减轻,睡眠改善。对照组 6 例乏力、纳差明显改善,睡眠恢复正常,体重增加,腹痛、腹胀消失; 7 例上述指标有所改善两组所比较有显著差异( P<0.01 )。说明治疗组患者的生存质量明显提高。血甲胎蛋白( AFP )治疗组较对照组明显下降( P<0.05 )。近期疗效观察发现,治疗组完全缓解 2 例,部分缓解 17 例,稳定 9 例,进展 6 例;对照组只有部分缓解 10 例,稳定 14 例,进展 8 例,两组比较有显著差异( P<0.05 )。毒副作用比较,治疗组白细胞下降情况明显少于对照组( P<0.01 )。鸦胆子油乳静脉给药后有两例出现低热, 1 例头晕。给予解热治疗,减慢滴速,用药 2 ~ 3 天后症状消失,未出现其他毒副反应。 (Source)


    经全国鸦胆子油乳抗癌研究协作组 -- 北京友谊医院、中国医大附院、白求恩医大附院、上海胸科医院、安徽医大附院等近 300 家临床医院观察 , 科研人员共观察了 16 个病种 ,30000 余例病人,重点对肺癌(包括肺癌闹转移、骨转移、淋巴转移)食管癌、胃癌、大肠癌以及膀胱癌、肝癌等进行了广泛的临床应用。大量的临床验证发现 , 鸦胆子油乳能与肿瘤细胞有较强的亲和力,并具有强有力的淋巴指向性,治疗肿瘤胸腹水的作用明显,能透过血脑屏障 , 不仅有抑癌作用,还有降低颅内高压的药理作用,它能提高病人干扰素水平,降低体内脂质过氧化反应 , 具有增强机体免疫功能和生物反应调节作用。


    用于肺癌、肺癌脑转移及消化道肿瘤,特别是对肺癌脑转移有较好疗效,对维持人体正常代谢功能的骨髓亦有保护作用,能升高白细胞 ( 如白细胞 300/nm 以下者仍可使用本品 ) 。 大剂量给药未尖肝、肾功能、血象及其它实质性器官的明显变化 , 配合化疗、放疗可减轻以上两种疗法的毒副作用。 (Source)

     

    Safety

    This herb impairs the gastrointestinal tract and the liver and kidneys, so it is inappropriate to use too much of it or to take it over a long period of time. It should be avoided or used carefully by those suffering from any gastrointestinal hemorrhage or from any liver or kidney disease. There are some suggestions that the sap of this species can cause a skin rash in susceptible people, but this has not been substantiated.

    毒理学: 鸦胆子挥发油有刺激性。其有毒成分为溶于水、具苦味的部分。鸦胆子仁或有效成分的大剂量,使动物内脏血管显著扩张,甚至出血;对中枢神经系统呈普遍的抑制现象;白细胞增多,多核细胞比率增加。治疗量在临床上常遇到的症状是恶心、呕吐,有时发生血压降低。去油鸦胆子对猫灌胃的最小致死量为 0.1g/kg 。鸦胆子中酚性成分的毒性最强,甙甲、甙乙次之,它们对小鼠皮下注射之半数致死量分别为: 0.65 、 10 、 74mg/kg 。死亡前呈全身抑制及四肢麻痹。毒性:鸦胆子甙给小鼠玻下注射的半数致死量为 7-10mg/kg ,猫及狗为 0.5-1mg/kg ,达此剂量可使动物的白细胞增多,心跳加快,呼吸减慢,肠胃等内脏充血,昏迷、惊厥,最后因呼吸衰竭致死;所含酚性化合物毒性最大,小鼠皮下注射的半数致死量为 0.65mg/kg 。鸦胆子仁的毒性强于鸦胆子油及壳,口服可致呕吐、腹痛、腹泻及尿闭,猫灌胃的最小致死量约为 0.1g/kg 。鸦胆子静脉注射对小白鼠的半数致死量为6250mg/kg 。鸦胆子煎剂对雏鸡肌肉注射的半数致死量为 0.25g/kg ,口服为 0.4g/kg 。鸦胆子粗提物注射给药时,除恶心、呕吐、腹泻、便血等消化道症状外,还呈现呼吸促迫、体温下降、肌肉无力、昏迷和死亡。鸦胆子油静脉乳毒性 小鼠 50 只(体重 20-21g ,雌雄兼用),尾静脉注射 l0% 鸦胆子油静脉乳,采用机率单位法测得半数致死量为 6250mg/kg 。亚急性毒性实验表明家兔给予鸦胆子油静脉乳 10g/kg ,其体重、肝功能、肾功能、血象均无明显变化。(Source)

    鸦胆子局部应用时,对皮肤和粘膜有强烈的刺激性。口服时常引起腹部不适、恶心、呕吐、腹痛、腹泻、坠胀和头昏无力,其发生率可达 78.3% 。鸦胆子外敷偶有过敏反应,有外敷引起过敏性休克,全身过敏。鸦胆子油有效成分油酸 3H 标记物的动物药代动力学小鼠或家兔静脉注射 H- 油酸静脉乳后的血药动力学变化符合二室开放模型。脏器分布有一定指向性,小鼠脾脏浓度最高,其次为肝、肺、心、、肾、大肠、小肠、胃。药物 24 小时经粪尿排出总量为 46.46% ,其中经粪排出 21.25%,经尿排出 25.21% 。

    Contraindications

    Fructus Bruceae should not be administered to children or pregnant women.

    Nursing mothers

    Excretion of Fructus Bruceae into breast milk and its effects on infants have not been established; therefore this drug should not be administered to nursing women.

    Pediatric use

    Fructus Bruceae should not be administered to young children.

    Other precautions

    No information available about general precautions or precautions concerning carcinogenesis, mutagenesis, or impairment of fertility; drug interactions; or drug and laboratory test interactions.

    Adverse reactions

    Some cases of anaphylaxis have been reported after external applications of the fruits of B. javanica . (Source)

     

     

     

       
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