含朱砂和雄黄小儿类中成药的药效与安全性研究进展

小儿类中成药疗效确切,相对安全,颇受儿科用药喜爱。然而,近年来,小儿类中成药安全问题越来越受世人关注。含雄黄/朱砂的中成药因其所含有砷、汞量大,远超世界各国对中草药重金属及有害元素的限量规定,其安全性备受质疑。本文综述了2015年版《中国药典》一部中收录的所有含朱砂、雄黄的小儿类中成药的使用现状,药效及安全性研究进展,并对这类中成药的使用进行展望,为科学认识和评价含有毒矿物药制剂提供参考。     

1995年版《中国药典》收载含朱砂、雄黄的中成药

１９９５年版《中国药典》收载含朱砂、雄黄的中成药杜常来李翠静山东威海市文登中心医院２６４４００朱砂、雄黄是２种有毒的中药，分别含可溶性汞盐和砷盐。汞进入人体７０％积集在肾脏，是其它组织的１５０倍，Ｔ１／２６５～７０ｄ，血汞浓度过高，可透过血脑屏障，直...     

安宫牛黄丸研究现状

综述了对安宫牛黄丸中朱砂和雄黄中总汞、总砷在动物体内的吸收、分布特点以及安宫牛黄丸及其简化方的药效学比较等试验 ,证明了在动物体内朱砂中的硫化汞和雄黄中的硫化砷只有少量可溶性的汞和砷被体内所吸收 ,而绝大部分硫化汞、硫化砷从消化道排除体外。而这部分可溶性的汞和砷很可能就是安宫牛黄丸朱砂和雄黄中的药理、毒理学的活性部分 ;作为构成朱砂和雄黄的主要成分硫化汞和硫化砷很可能是既不被体内吸收 ,又无任何药理活性的成分。这就给降低安宫牛黄丸中重金属的含量提供了可能。也为一大批含有重金属的中成药降低重金属含量作出了有意义的探索。     

含朱砂口服中成药中汞的生物利用性及安全性评价

目的 从生物利用性角度评价含朱砂中成药中汞的潜在健康风险.方法 火焰原子吸收法(FAAS)测定含朱砂中成药总汞含量,体外消化透析法模拟人体胃肠消化,氢化物发生-原子荧光光谱法(HG-AFS)检测得到含朱砂中成药中汞生物利用性相关数据.结果 6种常用含朱砂中成药在人工胃液中汞溶出率在0.14%～1.96%范围内,小肠阶段汞可接受率为0.003 8%～0.011 7%.基于汞在人体的半衰期和蓄积中毒量,反推导出含朱砂中成药中汞元素的安全阈值为每人每天0.099 mg.结论 综合考虑6种常用含朱砂中成药的汞含量水平、服用剂量、服用频次等,说明口服含朱砂中成药引起汞暴露的安全风险性较低.     

中成药雄黄朱砂配伍规律及其毒性研究

目的雄黄和朱砂是我国传统中药中常用的矿物药,为了更好的研究含有雄黄和朱砂的中成药的配伍规律、质量评价等。方法本文查阅含有雄黄和朱砂的中成药的中外文文献。结果 2015年版《中国药典》中,含有雄黄的复方有34个,同时含有雄黄和朱砂的复方有23个,含雄黄和朱砂的中成药主要分两种,口服和外用。雄黄和朱砂均为有毒中药。配伍过程中可增毒或减毒。结论研究结果可为含有雄黄的中成药的进一步研究提供依据。     

牛黄解毒片的安全性评价

含雄黄的牛黄解毒片用于临床已有800余年历史,但由于雄黄含砷,近年来国内外对其关注度高、争议大。对含雄黄的传统中成药而言,目前存在2个认识误区,其一是把雄黄毒性与砒霜相提并论,其二将雄黄贬得一无是处,可有可无,要求从复方中将其去除。含雄黄的牛黄解毒片到底有多毒?该文结合牛黄解毒片的研究进展对此作一综述,并提出不同见解:①以总砷为标准评价含雄黄中药的安全性不妥;②雄黄的服药量和服药时间的长短决定其毒性的大小;③雄黄是中药复方中的有效成分之一,应作深入研究来决定其取舍。对诸如牛黄解毒片等所含雄黄中成药的经典方剂,应该以严谨的现代科学依据加以评价,才能指导合理、安全应用。     

重视朱砂、雄黄对孕妇、小儿的毒副作用

朱砂。雄黄是两种有毒的中成药，我国传统中成药中，不少品种使用了朱砂、雄黄。1995年版药典一部收载了含朱砂、谁黄的中成药51种，其中小儿药20种约占39．00％，因此朱砂、难黄在孕妇、／J’）L的临床应用中，应重视毒副作用。朱砂、雄黄分别含有可溶性汞盐和砷盐，对人体危害性极大。朱砂对肝肾损害最严重，特别是肾脏，汞进入人体70％积集在肾脏，是其它组织的150倍，排泄极其缓慢，T人65—70d，血汞浓度过高，可透过血脑屏障，直接损害中枢神经，严重的可致痴呆症或死亡。据报道朱砂对孕免试验发现孕兔胎盘含汞最高，其次是肝、肾、…     

朱砂毒性、质量控制与合理使用

朱砂作为传统中药,至今应用十分广泛。随着临床实践不断发展,对朱砂的认识也逐渐加深,经历了从"无毒"到"有毒"的过程。目前对朱砂和含朱砂制剂的质量和疗效评价主要以总汞含量为指标,但这会导致其毒性被放大,临床应用的安全性遭到质疑,不良反应案例增多,严重影响到临床的使用。为此,本文就朱砂的临床药效、毒性认识及质量控制等进行综述,为朱砂在中成药中的药用价值评价提供参考。     

安宫牛黄丸中朱砂和雄黄的药理作用特点与安全性评价

目的:研究安宫牛黄丸中朱砂、雄黄在复方中的药效学存在的必要性和安全性,明确汞和砷在成药中和体内的化学存在形态,以及它们的药代动力学特点.方法:利用化学手段首次合成了若干个化学结构明确的汞和砷的络合物,并以此为对照物,对汞和砷在安宫牛黄丸成药中、大鼠血液以及组织器官中的化学存在状态均进行分析检测.并采用与安宫牛黄丸药效学相关的多项指标,对安宫牛黄丸及其简化方(安宫牛黄丸去掉朱砂和雄黄)进行了药效和毒理学的比较研究,采用药代动力学的方法研究汞和砷在大鼠体内的吸收、分布、血药浓度和排泄.结果:建立了简便、快速合成汞、砷络合物的方法,并揭示了安宫牛黄丸中汞、砷在体内外的化学存在状态;药代动力学研究证明了朱砂和雄黄中的HgS和As2S2为不被机体所吸收的无活性成分,而其生物活性成分可能为酸可溶性或水可溶性汞和砷部分;经镇静、抗惊厥、解热、缺氧模型以及毒性试验等多项药理学指标证明,安宫牛黄丸原方的药理学作用和简化方无明显统计学差异.结论:安宫牛黄丸中朱砂和雄黄的主要成分HgS和As2S2是不能被机体所吸收的无活性成分,而其生物活性成分(具有一定的药效学作用)为酸可溶性的汞和砷部分,药理学试验说明安宫牛黄丸和简化方未见明显区别.     

朱砂、雄黄的不良反应及预防

朱砂、雄黄是两种矿物药 ,它们既有确切的疗效 ,又有较强的不良反应。笔者就朱砂、雄黄的不良反应 ,探讨含朱砂、雄黄中成药的应用现状及存在问题。1　朱砂的不良反应　　朱砂系天然的辰砂、砂石 ,主要成分是硫化汞(Hg S含量约占 96 %) ,具有镇静安神作用 ,临床用于心悸易惊 ,失眠多梦 ,疮疡肿毒等病症。朱砂的毒性主要来源于朱砂中含有的游离汞 ,Hg2 + 与蛋白质的巯基有很强的亲合力[1] ,它与血液中的血红蛋白和血浆蛋白结合并随血液循环到达人体的各组织器官。有文献报道[2 ] ,朱砂对肝、肾的损伤最严重 ,特别是肾脏 ,汞进入机体后 70 %…     

Chemical form of metals in traditional medicines underlines potential toxicity in cell cultures

Ethnopharmacological relevance

Mercury (Hg) and arsenic (As) are frequently found in traditional medicines as sulfides, such as cinnabar (HgS) and realgar (As₄S₄). There is a general perception that any medicinal use of such metal-containing remedies is unacceptable. An opposing opinion is that different chemical forms of arsenic and mercury have different toxic potentials.

Aim of the study

To clarify this question, cinnabar, realgar, and cinnabar- and realgar-containing traditional medicine An-Gong-Niu-HuangWan (AGNH), were compared to well-known mercurials (HgS, HgCl₂ and MeHg) and arsenicals (As₂S₂, As₂O₃, NaAsO₂, and Na₂HAsO₄) for their cytotoxicity in human and rodent cell lines.

Materials and method

Cultured cells derived from target organs such as brain (HAPI) and liver (Hep3B, HepG2 and TRL1215) were treated with chemicals for 48 h and cytotoxicity was determined by the MTS assay.

Results

MeHg was most toxic with LC₅₀ of 4-20 μM, followed by NaAsO₂ (LC₅₀, 25-250 μM) and HgCl₂ (LC_50, 50-100 μM), Na₂HAsO₄(LC₅₀, 60-400 μM), As₂O₃(LC₅₀, 30-900 μM), and As₂S₂ (LC₅₀, 100-500 μM). In comparison, the LC₅₀ of realgar ranged from 250 to1500 μM; whereas cinnabar or HgS were approximately 20,000 μM and the toxicity of AGNH was in the range of 1500-8000 μM. Approximately 5000-fold differences exist between MeHg and HgS, and over 10-fold differences exist between NaAsO₂ and As₄S₄.

Conclusions

Chemical forms of metals are important factor in determining their toxicity in traditional medicines, both cinnabar and realgar are much less toxic than well-known mercurial and arsenicals.     

In vitro studies on dissolved substance of cinnabar: Chemical species and biological properties

Cinnabar is one of traditional Chinese medicines widely used in many Asian countries. It is also a medicine with potential toxicity especially when taking overdose. Up to date, studies on the mechanism of the biological activity of cinnabar were still insufficient.

Aim of the study

To investigate the possible bioactive species from cinnabar after oral administration, which is the fundamental of biological effects of cinnabar.

Materials and methods

Under mimetic intestinal and gastric conditions, the chemical components dissolved from cinnabar were analyzed by infrared spectroscopy (IR) and Raman spectroscopy. Furthermore, binding of mercuric species of cinnabar extractions to human serum protein (HSA) was characterized and their intestinal permeability was determined using the Caco-2 cell monolayer. The cytotoxicity of cinnabar extractions was assessed on human kidney-2 (HK-2) cell.

Results

Major dissolved species included mercuric polysulfide (i.e. HgS₂(OH)⁻ and Hg₃S₂Cl₂). The apparent permeability coefficient (P_app) of mercuric polysulfides was (1.6 ± 0.3) × 10⁻⁶ cm/s, which is slightly lower than that of mercuric chloride (HgCl₂). Unlike HgCl₂, mercuric polysulfides exhibited two tightly binding sites to HSA and had little effect on viability of HK-2 cells.

Conclusion

Mercuric polysulfides, as the major dissolved components, may serve as the active species of cinnabar exhibiting pharmacological and/or toxicological effects.     

朱砂的药理及毒理机制研究进展

朱砂及含朱砂的中成药疗效确切,其有毒无毒的问题自古争论至今仍无定论.早期文献综述较多报道朱砂药效或毒性的作用结果,少有关于机制方面的研究.近年来,一些研究者开始探讨朱砂药理及毒理作用机制,以评价朱砂的安全性及其在中药复方中的药效学必要性.本文对2000年以来国内外朱砂作用机制的研究进行评述.     

Cinnabar is not converted into methylmercury by human intestinal bacteria

Ethnopharmacological relevance

Cinnabar (Cin), a naturally occurring mercuric sulfide (HgS), is a mineral widely used in traditional Chinese medicine throughout history. As for the toxicity of cinnabar, one important assumption is that cinnabar may be transformed into highly toxic methylmercury by gastrointestinal flora. There is no evidence in humans to support this assumption.

Aim of the study

To investigate the biotransformation of cinnabar (HgS) in the human intestinal bacteria with modern analytical techniques.

Materials and methods

A gas chromatograph, equipped with electron capture detection (GC-ECD) and mass spectrometry (GC-MS), were used to detect the formation of methylmercury after incubation of cinnabar with human intestinal bacteria. The content of soluble mercury in the bacteria media was determined by cold vapor-atomic absorption spectrometry (CV-AAS). In addition, X-ray absorption near-edge structure spectroscopy (XANES) was used to confirm the possible transformation of cinnabar in the bacteria media, and under mimetic intestinal condition by measuring the species of sulfur and mercury in the reaction extraction of cinnabar and Na₂S mixture.

Results

No methylmercury was detected by both GC-ECD and GC-MS, which suggest that cinnabar (HgS) is not methylated in the human intestine. A small amount of soluble mercury was found to be released in the flora medium of HgS or cinnabar by CV-AAS. The XANES analyses revealed that polysulfides exist in the flora medium, and the simulated results showed that the products by incubating cinnabar with Na₂S were mercuric polysulfides.

Conclusion

These results showed that under gut flora conditions cinnabar would be transformed into mercuric polysulfides rather than methylmercury. Our work provides evidences of nontoxic transformation of cinnabar in the human intestinal bacteria.     

A report on the composition of mercurials used in traditional medicines in Oman

A brick red powder, used by a ‘native physician’ (a practitioner of traditional medicine in Oman) to treat a female patient for vitiligo, has been analysed by X-ray powder diffraction and scanning electron microscopy (S.E.M.). It was found to be a mixture of cinnabar (HgS) and calomel (Hg₂Cl₂). Symptoms of acute mercury poisoning resulted from the patient repeatedly breathing in elemental mercury vapour after this brick red powder and elemental mercury encased in a lime, were thrown on an open fire in a closed room. The patient also presented with central nervous system toxicity which improved gradually after treatment with Dimercaprol was discontinued. The use of mercurials as traditional medicines in Oman is briefly reviewed; as is the variation in literature values for ‘normal’/‘abnormal’/toxic levels of mercury in human blood.     

黄曲霉毒素B1免疫快速检测技术研究进展及其在中药中的应用

黄曲霉毒素B1(aflatoxin B1,AFB1)是由产毒真菌(如黄曲霉和寄生霉菌)产生的有毒次级代谢产物,具有致癌、致畸、致突变作用。研究表明AFB1广泛存在于农作物、食品、饲料甚至中药中,对人类健康造成了严重的安全隐患。建立一系列适用于不同基质中AFB1的多种快速检测技术,为预防和控制食品与药品的安全、保障人类健康方面具有重要意义。随着小分子免疫技术的不断提高,近年来各种检测形式的AFB1免疫快速技术被开发利用到现场快速检测领域,该文系统综述了我国现行有效的AFB1检测相关标准及近年来一些地区和国家等对中药材中黄曲霉毒素的限量标准情况,这些限量标准主要针对食品、饲料及一些易污染中药材中的黄曲霉毒素,而研究表明除了限量标准进行规定的中药材品种外也存在一些药用植物及其产品也有被黄曲霉毒素污染的情况。并对AFB1抗原抗体制备技术,以及基于抗原抗体特异性识别功能的快速检测方法包括酶联免疫吸附法、亲和色谱法、荧光免疫法、化学发光免疫法和新型免疫传感器法的开发及应用进行了归纳总结与对比。以期为中药规范化种植、中药集散贸易市场、药店医院、中药质量监管等方面形成快速、准确、灵敏的检测技术标准提供参考,确保中药的质量安全。     

佐太和HgS对药物代谢酶和转运体基因表达的影响

藏药佐太(主要含β-HgS)和中药朱砂(96%HgS)是传统医药中的配伍成分,其含重金属(汞)的安全问题和中西药合用时的相互作用问题日益受到关注。本实验就其对药物代谢基因的影响进行了研究。小鼠连续7 d口服给予不同剂量佐太、HgS(10,30,100,300 mg·kg-1),或氯化汞(Hg Cl2,33.6 mg·kg-1),RT-PCR检测药物代谢酶和转运体蛋白相关基因表达。佐太和HgS对Ⅰ相(CYP1A2,CYP2B10,CYP3A11,CYP4A10)和Ⅱ相(UGT1A1,UGT2A3,SULT1A1,SULT2A1)药物代谢酶以及转运体蛋白(OATP1A1,OATP1A4,OATP1B2,OATP2B1,MRP1,MRP2,MRP3,MRP4)均无明显影响,而Hg Cl2显著上调CYP2B10,CYP4A10,UGT1A1,UGT2A3,SULT1A1,SULT2A1,OATP1A4,MRP1,MRP3,MRP4,对OATP1A1有抑制作用。综上,佐太和HgS在300 mg·kg-1的剂量下对肝脏代谢基因的表达没有产生明显的影响,而1/10等汞量的Hg Cl2则明显上调或改变Ⅰ相、Ⅱ相药物代谢基因和转运体基因的表达。     

含朱砂中成药中甲基汞和乙基汞含量的HPLC-ICP-MS法检测

目的建立HPLC-ICP-MS联用技术测定含朱砂中成药中甲基汞和乙基汞含量的方法。方法采用盐酸提取,二氯甲烷萃取,水封吹氮浓缩等处理,利用高效液相色谱分离,最后由ICP-MS检测甲基汞和乙基汞含量。色谱柱为GRACE的Altima HP C18(5μm,150 mm×4.6 mm),流动相为含有5%甲醇,0.06 mol/L乙酸铵,0.1%半胱氨酸的水溶液。结果 19种含朱砂中成药中仅牛黄千金散检出甲基汞。甲基汞和乙基汞的线性范围均为0～50 ng/ml,相关系数大于0.999,检出限分别为0.5,0.4 ng/ml。分析龙虾肝胰脏粉标准样品TORT-2中甲基汞的回收率为84.0%,RSD为8.3%。结论该方法前处理简单高效、线性范围宽、精密度较好、准确性较高,适用于含朱砂中成药中甲基汞的测定。