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Comparative study on the aristolochic acid I content of Herba Asari for safe use.

Abstract

Herba Asari (Xixin, Manchurian Wildginger, Asarum spp.) is a traditional Chinese medicinal herb commonly used as a crude drug and an ingredient in patent medicines. The herb contains aristolochic acid I (AA-I), which has recently caused several incidents of poisoning in Hong Kong. Therefore, the safe use of Asarum is questionable. The present study was undertaken to assess the levels of AA-I using liquid chromatography-mass spectrometry (LC/MS) in different medicinal parts of Herba Asari and some proprietary Chinese medicines (PCM) containing it as an ingredient. The AA-I content in the aerial and root portions were compared, in the form of water and methanolic extracts. The results showed that all the aerial portions of Herba Asari generally contain higher levels of AA-I than the roots (in water extract: 0.08 [+ or -] 0.06 [micro]g/g of root and 0.32 [+ or -] 0.021 [micro]g/g of aerial), and the methanolic extracts typically contained more AA-I than the water extracts. Moreover, all the three PCM studies showed negligible amounts of AA-I (containing 0.03 [+ or -] 0.006 [micro]g/g). Therefore, the root portion of Herba Asari was recommended for prescription as a decoction instead of grinding it into powder for oral administration.

[C] 2008 Elsevier GmbH. All rights reserved.

Keywords: Aristolochic acid I; Herba Asari; Asarum: Aristolochia; Liquid chromatography--mass spectrometry

Introduction

An incident of aristolochic acid (AA) poisoning reported in Hong Kong recently has prompted governments worldwide to ban herbal medicines containing AA (Department of Health, 2004). Therefore, the Department of Health, HKSAR has announced that importation and sale of Chinese crude drugs (herbs) and related products (patent medicines) containing AA would be prohibited. In fact, based on the emergence of AA poisoning, most countries or regions have taken measures to prevent the recurrence of similar incidents by banning all herbs, drugs or preparations containing AA. In Britain, the government has forbidden the use of Aristolochia as a medicinal herb or as an ingredient in medicinal products as well as the use of any herb likely to be confused with Aristolochia. The US FDA has also prohibited the import of the preparations of all medical herbs from Aristolochia and those potentially confused with the herbs from Aristolochia. In the FDA's prohibited plant list, the AA-containing plants also include species of the genus Asarum (Fam. Aristolochiaceae). Herba Asari is precisely such a herb. Therefore, Herba Asari has also been drawing attention on its safe use.

Herba Asari is one of the most commonly used herbs in Chinese medicine therapy. Its application was first recorded in the Shennong Compendium of Materia Medica (Shennong Bencaojing) and nowadays widely used in the treatment of cough and dyspnea, headache, rheumatic arthralgia, sinusitis and toothache (Drew et al., 2002). While Herba Asari has been used as a herbal medicine for centuries, the part of plant in use has changed in recent years (Cai and Li, 2001). Traditionally, as recorded in the Shennong Compendium of Materia Medica, the medicinal part of Herba Asari is the root. Today, in Singapore, Japan, South Korea and Taiwan, the root is still used. However, in Mainland China since 1950s, people began using the aerial part as a result of the drastic reduction in available plant resources of Asarum. Since 2005, the Chinese Pharmacopoeia has changed the medicinal parts of Herba Asari from entire plant to root and rhizome. Nowadays the plant sources of Herba Asari are recorded as the three species of the genus Asarum: A. heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag., A. sieboldii Miq. var. seoulense Nakai or A. sieboldii Miq. (The State Pharmacopoeia Committee of China, 2005). The same medicinal parts of Herba Asari are also recorded in the Japanese Pharmacopoeia. Moreover, the regulation of purity test described in the Japanese Pharmacopoeia stating that the terrestrial parts such as leaves and petioles should not be prescribed (Society of Japanese Pharmacopoeia, 2001). However, Herba Asari is still sold as either in the form of root or entire plant in the herbal market of Hong Kong.

Until recently, the comparative pharmacological activities between the entire plant and the root have yet been studied and more importantly there still exists a void for the relative safety concern of the various medicinal parts. On the other hand, it has been found out that among the 158 samples of commercial Herba Asari collected from 28 provinces/cities in China, only three quarters are correctly derived from the species as specified in the Chinese pharmacopoeia (Cai et al., 1996). Its potential ban would be a matter of serious consequence to both of the local population and herbal medicine industry.

The experimental results proved that AA, especially aristolochic acid I (AA-I, Fig. 1, 8-methoxy-3,4-methylenedioxy-10-nitro-1-phenanthrenecarboxylic acid) is nephrotoxic, carcinogenic and caused gene mutation (Liu et al., 2003; Nortier et al., 2000; Lord et al., 2004; Sato et al., 2004). In previous reports, AA-I have been found in some plants from the genus Asarum by HPLC or LC-MS method (Hashimoto et al., 1999; Schaneberg et al., 2002; Schaneberg and Khan, 2004; Jong et al., 2003; Jiang et al., 2004). However, the contents of AA-I in the different medicinal parts of those plants are not compared. Moreover, the contents of AA-I were detected in the methanolic extracts of herbal medicines but none of these studies worked on aqueous extract. It is worthnoting that herbal medicines were often used in decoction form.

[FIGURE 1 OMITTED]

A first approach to develop a sensitive method to prove the presence or absence of aristolochic acids in Chinese herbs was undertaken by Blatter and Reich (2004) and Wagner et al. (2004).

In the present study, a standard analytical protocol from USFDA was optimized for the comprehensive evaluation of AA-I contents in various plant portions of Herba Asari including the entire herb, aerial part, stem and root (Flurer et al., 2002). The aim was to obtain an overall picture about the distribution of AA-I in various parts of the herb and to associate this with the safe use of medicinal parts. The levels of AA-I extracted from these plant parts were also compared using aqueous (decoction) and organic extractions for the first time. Furthermore, the contents of AA-1 in three well-known proprietary Chinese medicines (PCM) containing Herba Asari as an ingredient were also firstly analyzed. At the same time, the common observed ranges of AA-I in various species of Aristolochia were also evaluated and compared with Herba Asari in our study.

Materials and methods

Materials

Plant samples were obtained from local herbal markets and supplied by the Department of Health, Hong Kong Special Administrative Region (HKSAR), and authenticated by Prof. Zhao Zhongzhen. Voucher specimens of all samples are deposited at the Hong Kong Baptist University Bank of China (HK) Chinese Medicines Centre.

Three PCM namely, Xiaoqinglong Formula, Jiuweiqianghuo Formula, and Duhuojisheng Formula, chosen to represent the manufactured preparations of Herba Asari, were purchased over-the-counter from a herbal shop in Hong Kong. All of these PCM claimed to contain aqueous extracts of Herba Asari as one of the ingredients.

Reagents and instrumentations

The chemical reference standard of AA-I was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). HPLC grade methanol, ammonium acetate, formic acid and acetonitrile were used. Water was obtained from a Milli-Q (Millipore, Bedford, MA, USA) water purification system.

The liquid-chromatography mass spectrometer used was a Perkins-Elmer SCIEX API365 LC/MS/MS system. An Alltech C18 column (5 [mirco]m, 250 x 2.1 mm) was used at room temperature of 20 [degrees]C. The voltages of electrospray, orifice and ring were maintained at 5 kV, 30 and 170 V, respectively. The flow rate of nebulizing gas was kept at 1.041/min, while the collision energy was 17eV. Nitrogen was used as the collision gas and its density was maintained at 1.56 x [10.sup.15]molecule/[cm.sup.2]. Quantitation method was selected reaction monitoring (SRM) and the procurer ion was m/z 359.1 ([[M + [NH.sub.4.sup.+] of AA-I).

Chromatographic conditions

A mixture of 5% methanol, 10 mM ammonium acetate and 0.1% formic acid (A) as well as 50% acetonitrile in methanol with 10 mM ammonium acetate and 0.1% formic acid (B) were used as mobile phase in gradient mode. The gradient elution of mobile phase was 60-20% A in 0-2min, 80-100% B in 2-12min and 100% B in 12-17 min. The flow rate was maintained as 200 [micro]l/min, and the injection volume was 25 [micro]l. AA-I was confirmed by the presence of a chromatographic peak at the retention time of standard AA-I that produces peak area ratios for the specified product ions.

Preparation of the test solutions by methanolic extraction

Samples of herbal materials were pulverized to fine powder. The weights of the root, aerial portion and entire plant of Herba Asari were about 1.5, 0.5 and 1.0 g, respectively. The weight of Caulis Aristolochiae Manshuriensis was about 20 mg and that of the three other Aristolochia samples were approximately 0.5 g. The finely powdered samples were extracted consecutively with 20, 10 and 10ml methanol with sonication for 60 min at 40 [degrees]C. The extracts were combined and centrifuged at 3000 rpm for 5 min. The supernatant was transferred into a 50 ml volumetric flask, added 2 ml of 10% formic acid/water solution and made up to the volume with methanol. The solution was filtered through a 0.45 [micro]m filter membrane and the filtrate was ready as the test solution. The sample solutions of Radix Aristolochiae Debilis, Fructus Aristolochiae, Herba Aristolochiae Mollissimae and Radix Aristolochiae Fangchi were diluted 20 times for determination.

Preparation of the test solutions by water extraction

The finely powdered samples (the weight of each portion of Herba Asari was about 1.0g, that of Caulis Aristolochiae manshuriensis was about 20 mg, and each of the other samples was about 0.2 g) were soaked for 20 min by 10 ml water in a 20 ml glass bottle and then boiled in a water bath for 40 min. The extracted solutions were then centrifuged at 3000 rpm for 5 min. The supernatants were transferred to a 10 ml volumetric flask and adjusted to volume with water. A 5 ml solution was extracted by equal volume of ethyl acetate, and the organic layer was subsequently dried under a stream of air. The residue of each part of the Herba Asari sample was reconstituted in methanol and the volume was adjusted to 1 ml. The residue of Caulis Aristolochiae Manshuriensis was dissolved in methanol and adjusted to volume in a 10 ml volumetric flask.

Each supernatant of the solutions of Radix Aristolochiae Debilis, Fructus Aristolochiae, Herba Aristolochiae Mollissimae and Radix Aristolochiae Fangchi were transferred into a 50 ml volumetric flask and adjusted to the volume with water. A 5 ml solution was extracted by equal volume of ethyl acetate, and the organic layer was then dried under a stream of air. The residue was reconstituted in methanol and the volume was adjusted to 10 ml.

Each of the above solution was filtered through a 0.45 [micro]m filter membrane as test solution.

Preparation of the PCM extracts

Xiaoqinglong Formula and Jiuweiqianghuo Formula: The measured amount of the crude drug was soaked 30min in 500ml water, boiled for 40 min, filtered and 400 ml water was added to the residue, then further boiled for 30 min and filtered. The filtrate was concentrated and transferred into a 50 ml volumetric flask and was adjusted to volume with water. For the concentrated water extracts, it was observed highly densed and the chromatographic background was too noisy for interpretation. Besides, AA-I was readily soluble in methanol and ethanol but poorly soluble in water; therefore, ethyl acetate was selected as the extraction solvent for concentrating the AA-I content. An aliquot of 40 ml water extract was back extracted consecutively with equivalent of ethyl acetate for three times. The ethyl acetate extracts were combined and dried by a rotary evaporator. The residue was reconstituted in methanol and adjusted to volume in a 2 ml volumetric flask. The solution was filtered through a 0.45 [micro]m filter membrane and the filtrate was ready as a test solution.

Duhuojisheng Formula: Similar extraction procedures were conducted as above but using 750 and 500 ml water, respectively, for the initial and repeated extraction. The two filtrates were combined and concentrated, then transferred into a 100 ml volumetric flask and adjusted to the volume with water. A volume of 80 ml of water extract was then back extracted by equal volume of ethyl acetate for thrice. The combined organic layer was dried by a rotary evaporator. The residue was reconstituted in methanol and adjusted to volume in a 2 ml volumetric flask.

The above solution was filtered through a 0.45 [micro]m filter membrane prior to chromatographic analyses.

Results and discussion

Optimization of mobile phase gradient

To find the optimal elution conditions, the different ratio of mobile phase system reported by USFDA has been tested. In the USFDA method, the mobile phase system of A mixture of 5% methanol, 10 mM ammonium acetate and 0.1% formic acid (A) as well as 50% acetonitrile in methanol with 10 mM ammonium acetate and 0.1% formic acid (B) were used. When the gradient elution of mobile phase was optimized as 60-20% A in 0-2 min, 80-100% B in 2-12min and 100% B in 12-17min in the present study, a complete separation of AA-I and other chemicals was successfully achieved (Fig. 2).

[FIGURE 2 OMITTED]

Method validation

The stock solution of AA-I was prepared at a concentration of 0.5mg/l in methanol-10% formic acid (4:1) solution. The stock solution was diluted in 20ml volumetric flasks to yield a series of standard solutions with concentrations of 0.00, 0.02, 0.05, 0.08, 0.15mg/l for method validation of linearity. The linear regression of the curve and the coefficient were calculated as y = 216721 x-346.46 ([R.sup.2] = 0.9971). Based on repeated injections of various levels of the AA-I reference standard, the detection limit was found to be 0.01 [micro]g/ml as a signal-to-noise ratio of 10.

Quantification of aristolochic acid I (AA-I)

In order to totally detect the content of AA-I in Herba Asari samples, the efficiency extracting AA-I was investigated by repeated extraction. After the present extract methods, repeated extraction with the same solvents offered no further advantage. Fig. 2 shows the total ion chromatograms of solvent blank, standard of AA-I and the methanolic extract of Herba Asari. The results showed that the AA-I contents in different medicinal parts of Herba Asari were 0.08 [+ or -] [+ or -] [mu]g/g (n = 3) of root, 0.32 [+ or -] 0.021 [micro]g/g (n = 2) of aerial and 0.17 [+ or -] 0.11 [micro]g/g (n = 2) of entire plant in waterr extracts, respectively (Table 1). As for the methanolic extracts, the AA-I contents were 1.09 [+ or -] 0.99 [micro]g/g (n = 3) of root, 9.02 [+ or -] 4.08 [micro]g/g (n = 2) of aerial and 3.75 [+ or -] 2.18 [micro]g/g (n = 2) of entire plant, respectively (Table 2). Evidently, the methanolic extracts contained more AA-I than the water extracts. Our results showed that the AA-I content of the aerial part of Herba Asari is always much higher than the of the root, which provide the reliable data for confirming the traditional use of Herba Asari. In this regard, the practice of using the root as medicinal part should be strictly adhered to as a beginning step for safety prescription of Herba Asari.
Table 1. Contents of AA-I for a list of crude drugs by
methanolic extraction

Species name Herb Medicinal Content of AA-I (a)
 I.D. part ([mu]g/gg)

 Sample and Mean
 duplicate

Asarum sieboldii Miq. A Root 0.20 0.19
var. seoulense Nakai

 0.19

Asarum heterotropoides B Root 2.01 2.16
Fr. Schmidt var.
mandshuricum (Maxim.)
Kitag.

 2.31

 B Aerial 11.65 11.91

 12.17

 B Entire 5.42 5.30
 plant

 5.17

 C Root 0.97 0.93

 0.88

 C Aerial 6.68 6.14

 5.59

 C Entire 2.36 2.21
 plant

 2.06

Aristolochia mollissima D Aerial 224.91 220.96
Hance

 217.01

 E Aerial 303.54 254.04

 204.53

 F Aerial 205.69 201.65

 197.60

 G Aerial 452.02 440.61

 429.20

Aristolochia manshuriensis H Stem 1951.90 1903.31
Kom.

 1854.72

Aristolochia fangchi I Root 36.36 36.42
Y.C. Wu ex L.D. Chou
et S.M. Hwang

 36.48

Aristolochia debilis J Root 529.20 535.40
Sieb. et Zucc.

 541.60

 J Fruit 538.52 544.41

 550.29

(a) The value is expressed in two decimal place.

Table 2. Contents of AA-I for a list of crude drugs by
water extraction

Species name Herb Medicinal Content of AA- I (a)
 I.D. part ([mu]g/g)

 Sample and Mean
 duplicate

Asarum sieholdii Miq. var. A Root 0.03 0.04
seoulense Nakai

 0.05

Asarum heterotropoides Fr. B Root 0.16 0.15
Schmidt var.
mandshuricum (Maxim.) Kitag.

 0.14

 B Aerial 0.33 0.34

 0.34

 B Entire 0.24 0.25
 plant

 0.26

 C Root 0.05 0.05

 0.05

 C Aerial 0.36 0.31

 0.26

 C Entire 0.08 0.09
 plant

 0.09

Aristolochia mollissima D Aerial 79.12 81.56
Hance

 83.99

 E Aerial 94.85 94.31

 93.76

 F Aerial 77.97 73.10

 68.22

 G Aerial 169.05 166.56

 164.06

Aristolochia manshuriensis H Stem 380.95 1375.60
Kom.

 370.24

Aristolochia fangchi Y.C. Wu I Root 16.97 15.10
ex L. D. Chou

et S. M. Hwang 13.23

Aristolochia debilis Sieb. et J Root 317.27 305.49
Zucc.

 J Fruit 261.37 263.98

 266.59

(a) The value is expressed in two decimal place.


Another aspect concerning the change in medical practice in recent centuries is about the prescribed dosage levels of Herba Asari. In the Song Dynasty, less than one "Qian" (a ancient weight units in China which was equal to 3.125 g) of Herba Asari was used each time in prescription, that is, the dosage of powdered root of Herba Asari should not exceed 3 g. Safrole, a constituent of the volatile oil in Herba Asari, has been shown to be carcinogenic to animal (Drew et al., 2002). Therefore, modern toxicology studies revealed that the toxic components in Herba Asari have greatly reduced after boiling in water for a considerable time during preparation of the decoction (Cai and Li, 2001). However, the information about the content of AA-I in Herba Asari containing in the decoction is not known. Moreover, nowadays in Hong Kong, the practice of using more than 3 g of Herba Asari is common in a single prescription, but poisoning phenomenon has not been observed. It has been reported that AA would have a significant risk factor for urothelial carcinoma, probably associated with the highest risk when the cumulative level exceeds 200 g crude drug of Aristolochia fangchi (Nortier and Vanherweghem, 2002). Recently, an incident of a 49-year-old male who displayed subacute rental failure induced by ingestion of herbal powder containing Herba Asari has been reported (Yang et al., 2006). In the present study, all the three PCM containing 3g Herba Asari studied contained negligible amounts of AA-I (containing 0.03 [+ or - ]0.006 [micro]g/g, n = 3, Table 3). All these concluded that Herba Asari should be consumed as a decoction instead of crude powder for oral administration. The results also provided evidence that AA-I has a lower solubility in water than methanol after prolonged boiling. Based on such results, Herba Asari is recommended for prescription as a decoction instead of grinding it into powder for oral administration.
Table 3. Contents of AA-I in three selected PCM by water
extraction

Proprietary Medicinal Quantity Quantity Contents
Chinese part used of Herba of the of AA-I in
medicine Asari claimed formula the formula
 in the formula (g) ([mu]g/g)
 (g)

Xiaoqinglong Entire 3 57 0.04
Formula plant

Jiuweiqianghuo Entire 3 36 0.03
Formula plant

Duhuojisheng Entire 3 90 0.03
Formula plant


Contrarily, our studies revealed that the levels of AA-I in the four crude herbs of Aristolochia were several ten folds higher than those observed in Herba Asari (Tables 1 and 2). The AA-I contents in the medicinal plants of Aristolochia varied from 15.10 to 1370[micro]g/g even in water extracts. Previous reports have shown that the Chinese medicines from Aristolochia used inappropriately or excessively would cause kidney failure and urethra cancer, such as nine cases of rapidly progressive renal fibrosis, among them two cases of end-stage renal failure related to the Chinese medicine Fangji derived from Aristrochia root, containing AA, have been reported in 1993 in Belgium (Vanherweghem et al., 1993). Similar cases of the plants from the Aristolochia genus inducing renal toxicity have also been reported in Poland, France, Britain and Korea (Wankowicz et al., 1996; Stengel and Jones, 1998; Lord et al., 1999; Lee et al., 2004). Therefore, it is reasonable that those crude drugs should be forbidden for use to avoid any further incident of poisoning from a safety point of view.

As a result, Herba Asari should be permitted to be used in herbal medicine practice. However, the root of Herbal Asari is the correct medicinal part, and it should be prepared as a decoction instead of grinding it into powder for oral administration to avoid AA poison.

Acknowledgement

The Department of Health of the Hong Kong Special Administrative Region funded this research and supplied all the samples.

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Zhong-Zhen Zhao (a), *, Zhi-Tao Liang (a), Zhi-Hong Jiang (a), Kelvin Sze-Yin Leung (b), Chi-Leung Chan (a), Hon-Yee Chan (c), Jaime Sin (c), Tim-On Man (c), Kwok-Wai Law (c)

(a) School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong Special Administrative Region, PR China

(b) Department of Chemistry, Hong Kong Baptist University, Kowloon, Hong Kong Special Administrative Region, PR China

(c) Chinese Medicine Division, Department of Health, Hong Kong Special Administrative Region, PR China

* Corresponding author. Fax: +85234112461.

E-mail address: zzzhao@hkbu.edu.hk (Z.-Z. Zhao).
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Author:Zhao, Zhong-Zhen; Liang, Zhi-Tao; Jiang, Zhi-Hong; Leung, Kelvin Sze-Yin; Chan, Chi-Leung; Chan, Hon
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9CHIN
Date:Sep 1, 2008
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