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Aristolochia Nephropathy

from: Deutsche Zeitschrift für Akupunktur 43(2000), 187-197
Axel Wiebrecht

Abstract

The possible harmful effects of traditional Chinese remedies to the kidney have attained broader public attention in Germany due to publications in the Deutsches Aerzteblatt and the SPIEGEL magazine and their subsequent echo in various papers and announcements. These reports revealed a strange mixture of truth, hoaxes, confusions, misinterpretations and ignorance. The present article suggests that the tragic cases of terminal kidney failure following a Belgian weight reduction program can not simply be attributed to Chinese herbs, even if they are involved. On the other hand it will be argued that Aristolochia species applied in the context of Traditional Chinese Medicine can cause severe nephropathy. The widely used term "Chinese herb nephropathy (CHN)" makes no sense as nephropathy is not a special characteristic of Chinese herbs, but one of aristolochic acid and Aristolochia species containing this substance, which appears in China as well as in Western and other countries. An estimate pertaining to France calculated a frequency of two cases of nephropathy in 1000 patients treated with remedies containing aristolochic acid. In the meantime similar reports have emerged in many countries.

In Germany all remedies containing aristolochic acid, i.e. all varieties of the Aristolochia species and preparations made from these as well were banned in 1981 because aristolochic acid is carcinogenic. The carcinogenic effect was also evident in the Belgian cases, and was brought to the attention of the international public by a report in the New England Journal of Medicine in June of 2000. The nephro­toxic effects were well known since the fifties. A dose evaluation shows that as a result of TCM treatment, a dosage of up to 7956 mg aristolochic acid may accumulate after three months, or as much as 63.650 mg after two years. These amounts exceed by far those attained in the West, when Herba aristolochiae clematidis or pure aristolochic acid (up to about 162 mg) was used. On these grounds the therapeutic use of Aristolochia species should definitely be rejected regardless of the ban in Germany and other countries. Pharmacies and pharmaceutical wholesalers should be held to higher quality standards to avoid confusion or errors pertaining to drugs, as well as to prevent contamination by heavy metals, pesticides or even pharmaceutical agents. Herbs that can be mistaken for Aristolochia species, such as Stephania tetrandra, should definitely be examined for the absence of aristolochic acid. Powders or other preparations from these herbs should be avoided. mg mg/d common daily dos

  mg mg/d common daily dose
Capsule A (3 per day, orally):           
     
Fenfluramin 17-25 42-75 60(-120)1
Diethylpropion 17-25 42-75 60-752
Meprobamat 0-50 0-150 600-16002

Capsule B (3 per day, orally):
     
Cascara powder 20-150 60-600 250-10003
Acetazolamid 24-45 72-135 75-5002
Belladonna extract 1-2 3-6 extract dependant
Stephania tetrandra 100-200 300-600(powder) 3000-9000 (drug)4
Magnolia officinalis 100-200 300-600(powder) 3000-9000 (drug)4

intradermal injections (1 per week):
     
Artichoke extract (Chophytol S) 0,2    
Euphyllin 0,5    
1 according to (40)  2 according to (10)  3 according to (71)  4 acoording to (5)
Tab. 1: Medication used in the Belgian slimming clinic from May, 1990 to May, 1992 (70)
Pharmaceutical Name Botanical Species Chinese Name TCM Category
Cort. Magnoliae Officinalis Magnolia officinalis Hou Po transf. dampness
Rad. Stephaniae Tetrandrae Stephania tetrandra- (Han) Fang Ji drain dampness
Rad. Aristolochiae seu Cocculi Aristolochia fangchi+ Guang Fang Ji drain dampness
  Cocculus trilobus-    
Caul. Mutong Aristolochia manshuriensis+ (Guan) Mu Tong drain dampness
  Akebia trifoliata    
  Akebia quinata-    
  Clematis armandii-- (Chuan) Mu Tong  
  Clematis montana-- (Chuan) Mu Tong  
Fruct./Rad. Aristolochiae Aristolochia debilis+ Ma Dou Ling(Fruct.) relieve cough
  Aristolochia contorta Qing Mu Xiang(Rad.)  
+ with evidence of aristolochic acid I und II (31)
- with no evidence of aristolochic acid I/II (31)
-- with no evidence of aristolochic acid (12)

Tab. 2: Compilation of pharmaceutical, botanical and Chinese names of the herbs and the categories to which they belong in the Traditional Chinese-pharmacotherapy according to (5, 52). 

   Belgium  France  Tardolyt®  TCM  Jackson et al.
 DD of herb [mg] 300-600   (270)-540  3000-90001    
 AA [mg/g herb]  0,65-1,56  3  1,07-9,822    
 DD AA [mg]  0,195-0,936  1,62  0,45-0,93  3,2-88,4  70-1404
 treatment period [d]  540  90-450  28-3605  7206  1-227
TD [mg] 110-505 146-729 25-162 2304-63650 140-4208
1 3-15g(5) or 4,5-9g(52) are quoted for Aristolochia fangchi , 3-9g(5) or 3-6g(52) for Aristolochia manshuriensis   2 according to (31)
3 according to(8)   4 body weight supposed as 70kg
5 according to (33) and (29)   6 treatment period of the English cases was 2 -6 years (36)
7 one case 45 days   8 one case 1029mg
DD = daily dose   AA = aristolochic acid   TD = total dose (cumulated)
Tab. 3: Estimation of doses of aristolochic acid given in the Belgium slimming clinic, of the French cases, of Tardolyt®, of Aristolochia fangchi or Aristolochia manshuriensis doses commonly used in TCM and of cases with acute application according to Jackson et al. (35). For Belgium and France the data from Stengel and Jones was used (57) giving a conservative estimation with 540mg powder as a maximum daily dose for France.

FDA prohibits Ephedra in Supplements

From: Deutsche Zeitschrift für Akupunktur 47(2), 2004, 54-56
Axel Wiebrecht

On February 6 in 2004 the FDA published a ban on dietary supplements containing ephedrine alkaloids, such as ephedrine or pseudo-ephedrine. This includes Ephedra (MA HUANG) as well as Pinellia ternata (BAN XIA) and Sida cordifolia, which is used in ayurvedic medicine and in Africa. The ban took effect 60 days after publication. The FDA explicitly states that Chinese herbs and herbal infusions, which are regarded as nutritional supplements in the USA, are not affected.

The Drugs concerned: Ephedra (ma huang), Pinellia ternata (ban xia), and Sida cordifolia

Ephedra has been used as a remedy for about 5000 years and is therefore probably the oldest pharmaceutical herb in continuous use in the world. Traditional Chinese Medicine (TCM) recognizes three herbs as "MA HUANG": The herb (herba) Ephedra sinica Stapf, E. equisetina Bunge, and E. intermedia Schrenk et Mey (1). In their monograph "Ephedrae herba" the commission E at the German BfArM (Federal Institute for Drugs and Medical Devices) names the following species which are or were commonly used in German pharmaceuticals: "Ephedra herb, consisting of the dried young leaves harvested in autumn of Ephedra sinica Stapf, Ephedra shennungiana Tang, or other similar kinds of ephedra" (2).

Rhizoma pinelliae ternatae or BAN XIA only contains small amounts of alkaloids. According to Chinese publications the total alkaloid content lies below 0.5%, and the ephedrine alkaloids only make up a part of that. Sida cordifolia, which is an important drug in Ayurvedic medicine, on the other hand contains higher levels of ephedrine alkaloids. However these levels should not be as high as those in Ephedra

USA: non-monitored use of Ephedra for weight-loss and performance enhancement

The reason for the banning of Ephedra in the USA is the high numbers of reports of side-effects after using Ephedra, which in the USA is mainly used for weight loss and enhancing athletic performance. This kind of use poses the risk of over dosage. The reports published in the literature and received by the FDA and manufacturers were evaluated in the RAND report. The most severe cases were those of death, myocardial infarctions, cerebrovascular accidents (apoplexy and cerebral hemorrhage), "other neurological" incidents, including epileptic fits and psychiatric problems (3). However the voluntary reports to the FDA were often so incomplete, that the causes can not be reconstructed sufficiently in all individual cases. The reason for this may also be that the use of dietary supplements does not require medical supervision and that the reports were often made by lay-people, including family members. In 98% of all cases the reports were incomplete, no less than 80.7% failed to specify the daily intake (4). The effects of Ephedra alone, even more so in combination with caffeine, for fast weight-loss has been proven by studies. Regarding the enhancement of performance, the data remains insufficient (3).

When looking at the cases of side effects, one needs to take into account that 2 to 3 billion (!) doses of supplements containing ephedrine alkaloids, are ingested every year in the USA (5,6). Consumption has increased dramatically in the last 10 years. According to estimates about 17.2 million US-citizens ingested non-prescription weight-loss drugs from 1996-1998. 2.5 million of those drugs contained Ephedra (7). Usually these are combination drugs, often containing other sympathomimetic substances such as caffeine (often in high doses) or yohimbine. The American laws dealing with dietary supplements are the most lax among the standards dealing with foodstuffs (7).

The most severe cases identified in the RAND report were so-called "sentinel events". This classification explicitly means that Ephedra or ephedrine as a cause has not been proven. These sentinel events were: 5 deaths, 5 heart attacks, 11 cerebrovascular accidents, 4 epileptic fits, and 8 psychiatric emergencies. About half of those cases were related to persons of 30 years or younger. Another 46 cases were classified as "possible sentinel events".

Among the reported cases there are only a few describing the use of Ephedra or ephedrine for the treatment of a disease, and in those cases the dosage was much too high. Apparently no serious cases concerning the supervised use of Ephedra in recommended dosages, including in TCM therapies, were reported in the USA.

Raised risk in combination with sympathomimetics

The reported cases - as far as that information was submitted - almost always reported a combination drug of Ephedra or ephedrine and another more or less sympathomimetic substance, such as caffeine (usually as an extract of plant origin), yohimbine and others, which might have an additive or synergetic effect. Competitive sports also have a strong sympathomimetic effect. The reduced ingestion of calories or fasting might also lead to a higher sensitivity regarding pharmaceutics. The cases of kidney damage linked to Aristolochia (8) or liver damage linked to other pharmaceutics suggest that here, these may also be contributing factors (e.g. 9). Also, looking at the mass consumption of Ephedra products, one might expect an unplanned co-medication with contraindicated drugs, such as MAO-blockers, asthma medication, or other sympathomimetics. The physician prescribing such a drug might not know of the patient's use of Ephedra or the patient does not know the possible risks. In addition there is a risk that the patient might increase the dosage in an effort to lose more weight, better athletic performance, or benefit from its psychotropic effect, especially since herbal products are often regarded as "harmless".

Use of Ephedra in TCM

The mass consumption in the USA is a culturally-specific phenomenon of a society in which the number of obese people is growing, while at the same time, aesthetic standards require women to be thin and men to be muscular. In addition, the Americans have very lax laws regarding dietary supplements. Therefore it is very difficult to draw conclusions from the reports regarding the supervised intake of MA HUANG or Ephedra. Since MA HUANG has a strong draining effect, no responsible TCM practitioner would prescribe it for weight loss or to anyone participating in competitive sports. Bensky and Gamble wrote: "use with caution in cases of deficiency with sweating or wheezing" at a time when the consumption of Ephedra had not yet reached these proportions (1). The western biomedical contraindications should be well-known. In the commission E monograph these are listed as: anxiety, restlessness, high blood pressure, angle-closure glaucoma, cerebrovascular diseases, prostate adenoma with urine retention, phaechromocytoma, thyreotoxicosis (2). If the patient suffers from cardiac problems or has a high risk of coronary heart disease, Ephedra should be avoided. The Centrum für Therapiesicherheit in der Traditionellen Chinesischen Arzneitherapie (CTCA, Center for Safety in Traditional Chinese Medicine Therapy) is preparing an evaluation of MA HUANG / Herba ephedrae.

What about Europe?

Manufacturers in the USA have already adapted to the new situation, and as consumer awareness has increased, now offer Ephedra-free products using the same labels. On the other hand there are more and more Ephedra products on offer via the Internet in Europe. For example: Ephedrine Super Caps by D&E, "the dietary supplement from the USA", "for people and athletes wishing to enhance their performance or simply lose weight". According to their labels they contain 850mg of MA HUANG extract, which means 50mg ephedrine; the recommended dosage is 1 to 2 capsules daily, for no more than 2 months. "It has been proven to stimulate the burning of fat and improves the senses". A warning is added stating that: "after ingestion no bio- or psychoactive substances should be taken", but at the same time they seem to encourage consumption: "Small doses of caffeine are tolerable and are even added to various ephedrine products, as it stimulates the liberation of fat cells from the fatty tissue." These capsules cost about €23 per 100 capsules. Sooner or later uncontrolled use of dietary supplements containing Ephedra might pose a health risk here in Europe. However, evidence suggests that the risk through prescription by qualified TCM therapists is negligible.

Literature:

    1. Bensky D, Gamble A (1993). Chinese Herbal Medicine. Materia Medica. Revised ed: Eastland Press, Seattle, Washington
    2. Kommission E (1991). Monograph Ephedrae herba (Ephedrakraut). Bundesanzeiger No. 11, 17th January, 1991
    3. Shekelle PG, Morton S, Maglione M et al. (2003). Ephedra and ephedrine for weight loss and athletic performance enhancement: clinical and side effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based Practice Center, RAND, under Contract No. 290-97-0001, Task Order No. 9). AHRQ Publication 03-E022. Rockville, MD: Agency for Healthcare Research and Quality; February 2003. Available at: http://www.fda.gov/OHRMS/DOCKETS/98fr/95n-0304-bkg0003-ref-07-01-index.htm
    4. Cantox Health Sciences International (2000). Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Im Auftrag des Council for Responsible Nutrition. December 19, 2000. Abrufbar unter: http://www.crnusa.org/cantoxreportindex.html
    5. United States General Accounting Office (GAO) (1999). Dietary Supplements: Uncertainties in Analyses Underlying FDA's proposed Rule on Ephedrine Alkaloids. GAO, Washington, DC. Zitiert nach(4)
    6. American Herbal Products Association (AHPA) (2000). Ephedra Survey Results: 1995-1999. Survey Administered & Results Compiled by: Arthur Andersen LLP prepared for the AHPA. April 28,2000. Zitiert nach (4)
    7. Fontanarosa PB, Rennie D, DeAngelis CD (2003). The Need for Regulation of Dietary Supplements - Lessons From Ephedra. JAMA;289:1568-1570
    8. Wiebrecht A (2000). Über die Aristolochia-Nephropathie. Dt Zschr Akupunktur 43:187-197
    9. Kurtovic J, Riordan SM (2003). Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med; 253:240-243

The Safety of Asarum – An Evaluation

Translated from the German by Friederike Wunschik from an article published in the Deutsche Zeitschrift für Akupunktur 54(2), 2011:47-50

Axel Wiebrecht

Abstract

Xi xin – Asarum Radix et Rhizoma – is a classical herb in Chinese medicine. It is of vital importance in various prescriptions and difficult to replace. After the discovery in the 1990s that aristolochic acid (AA)-I and -II were associated with severe nephropathy and urothelial carcinoma, aristolochic acid was also found in Asarum ssp. However the amounts of AA-I and AA-II cited are mostly very small and occasionally below the limit of detection. In comparison, non-officinal Asarum crispulatumcontains high amounts of aristolochic acid. Because of the aristolochic acid content, both Switzerland and Germany banned the medicinal use of Asarum in 2010. The Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM), in banning the herb, argues that the only acceptable risk is a 50 percent life-time chance of developing a tumour in one in 1,000,000 persons after two years of drug-administration. This risk tolerance is extremely low when compared to that of conventional drugs or everyday hazards. A more realistic risk calculation might take into account the risk of death to the general population caused by the nuclear radiation that Germans are allowed to be exposed to each year by nuclear facilities. In such a calculation, the health risk posed by xi xin could, by prescribing a maximum length of administration and enforcing strict quality control measures on xi xin medicines, be reduced to a very tolerable level. A total ban of Asarum seems disproportionate.

Key words: Chinese herbal medicine, Asarum, Xi xin, aristolochic acid, nephropathy, tumor risk, adverse drug event

Introduction

Xi xin – Asarum Radix et Rhizoma – is a classic herb in Chinese medicine. It is mentioned in the first-known Materia Medica, the shen nong ben cao jing from the late Han dynasty. The Chinese medicine pharmacopoeia describes xi xin as acrid and warm, opening the exterior, dispelling cold, expelling Wind, Cold, Dampness and Phlegm, and relieving pain. It is predominantly used in the treatment of colds, cough with thin sputum, and also for head- and toothaches, as well as joint pain. It is an essential herb needed to treat a variety of diagnoses and is difficult to substitute.

Administration of this herb has traditionally been cautious; the official daily dosage of the raw herb lies between 1 and 3 grams [1]. Overdose may lead to unwanted side-effects or even death [2, 3]. Toxic reactions are due to safrole contained in the herb [3]. Safrole is considered to be a weak hepatocarcinogen and genotoxic. The safrole content is reduced through the process of decoction and by this means achieves acceptable levels [4].

A completely different set of problems arose during the 1990s, when aristolochic acids in Aristolochia herbs were found to be associated with many cases of terminal nephropathy in patients treated at a Belgian weight-loss clinic. After this incident, other cases were discovered worldwide [5]; many of those developed urothelial carcinomas [6]. Aristolochic acids were already known to be potent carcinogens and in Germany, herbs containing aristolochic acids were banned in 1981 [5]. While various countries were implementing safety measures and bans, Asarum plants were found to contain aristolochic acid. However, the levels of aristolochic acid in these plants, if it was detectable at all, were definitely lower than the levels measured in Aristolochia herbs.

To reduce risk, the officially used part of the plant, that at first had been modified to herba – the aerial parts – due to availability issues, was changed in the Chinese Pharmacopoeia to radix et rhizoma in 2005, because these parts contain less aristolochic acid. In 2004 Hongkong had already banned the sale of herba or planta tota ofAsarum, allowing only the use of radix [7].

Aristolichic acid in Asarum

Table 1 shows the levels of aristolochic acid documented in the Asarum species used in Chinese medicine [8-12]. Almost all the levels of aristolochic acid-I (AA-I) for those parts of officinal xi xin ssps. allowed for use in drugs (radix et rhizoma or just radix) are below 1 µg/g (marked in green); only one value of 2.16 µg/g is higher. The levels of aristolochic acid-II (AA-II) are generally lower and were only taken into consideration in some of the studies.

Zhao et al [12] compared the levels of AA-I in several samples of watery extract with those of methanolic extract. In a methanolic extraction the extract retains large amounts of the aristolochic acid of the plant, while water extracts closely resemble a decoction, depending on the extraction conditions. In this case the herb was soaked in water for 20 minutes and then boiled for 40 minutes. As shown in Table 1, water extraction reduces the level of aristolochic acid; when using radix it is reduced by a factor of 4.7 to 18.6. Granules are made from watery extracts and therefore equivalent reduced levels of aristolochic acid can be inferred. Pulverised raw xi xin should not be ingested, as it contains the full amount of aristolochic acid.

Other parts of the plant, specifically the aerial parts (herba) or the entire plant (planta tota), contain much higher levels of aristolochic acid. The highest published value is a troubling 142 µg/g. More dramatic values are found in non-officinal species, namely Asarum crispulatum, found in Sichuan and used as a local variant for xi xin, which contains a whopping 3,376.9 µg/g [9]. This value corresponds to a medium value found in the Aristolochia-herbs [8]. This shows how crucial the use of officinal drugs with valid confirmation of identity is.

Banned by the German BfArM

On July 22nd 2010 the use of all plants belonging to the Asarum species in drugs was banned in Germany by decree of the Federal Institute for Drugs and Medical Devices (BfArM) [13]. The cause of this was the detection of AA-I in homeopathic mother tinctures of Asarum europaeum with levels of 5.1 and 2.7 µg/g. The decree also mentions studies that found higher levels of aristolochic acid, among them the above-mentioned values for Asarum crispulatum.

In its risk assessment the BfArM assumes a tolerable cancer lifetime risk of 1:1,000,000. Accordingly, with a linear dose-reaction-model for two years of administration, a virtually safe dose of 0.36 ng aristolochic acid per diem can be calculated. For homoeopathic remedies the above-mentioned highest documented level of aristolochic acid of 3,377 µg/g in Asarum ssp. is used as a base-value. Therefore a tolerable dose is not achieved until D9, and only at D11 is the dose considered non-hazardous. Assuming the lowest published level of aristolochic acid in a decoction of 0.04 µg/g made by officinal asarum medicines, then the “virtually safe dose” is just exceeded at 1g xi xin. But: are these assumptions realistic?

Unrealistic safety guidelines

To recap: the BfArM considers that the only acceptable risk for ingestion of aristolochic acid through herbal medicines is a 50 percent life-time chance of developing a tumor in one in one million cases. This safety guideline is however far more restrictive than the risks tolerated in conventional drugs.

According to the study carried out by the WHI, hormone replacement therapy was associated with 700 cases of coronary heart disease, 800 strokes, 1,800 cases of venous thrombosis, and 800 cases of invasive breast cancer in one million healthy women per year (!). The 500 hip fractures and 600 colorectal cancers less in those women are not on the scale of the negative results of that study [14]. Hormone replacement therapy is still approved; a discussion of whether this is justified or not is beyond the scope of this article. According to two three-year studies, the anti-diabetic drug Pioglitazone - which is controversial because of the increased risk of heart failure and fractures associated with it - increased the incidence of bladder cancer by 0.3% (absolute value) compared to those receiving placebo or glibenclamide. This is an increase in carcinomas of 3,000 in one million cases in this three-year period [15].

The difference in tolerated risk becomes painfully apparent, when considering every-day risks. Tobacco smoking at the time of first data collection, for instance, if one extrapolates the results of a twenty-year British study, was the cause of death in 99,485 out of 1,000,000 adults (extrapolation according to [16]). Nevertheless, tobacco products are widely available to all adults.

Of course, risk assessment should always take into account the benefits. However, the government drug authorities seem to employ an all-or-nothing rule: if the efficacy of a drug– however small it may be – is proven with an Ia or even an Ib evidence level then the occasional high risk is accepted; while a nearly-zero-risk-tolerance is in place concerning drugs with only experience-based efficacy. This methodology is inacceptable and half-baked. As the tobacco example shows – other examples would include alcohol, air pollution, and similar factors – this purism is not applied to other areas, although this does not at all mean that the lax attitude to these health-risks should be endorsed. One gets the distinct impression that conventional and complementary medicine are being measured with different yardsticks, which is probably due to the prevailing medical paradigm.

There are other ways of minimizing risk

A more realistic but nevertheless highly safe risk reduction could, for example, entail the following: Taking the BfArM’s way of calculation (which shall not be discussed here) and assuming a 50% life-time likelihood of tumour not in 1 in 1,000,000, but in 1 in 10,000 patients, this measure can be met by not exceeding a daily dosage of 3g raw herb and by limiting the period of administration to a maximum 6 weeks, if you apply a decoction made in standardised manner using herbs with a content of less than 0.1 µg/g of aristolochic acid (AA-I and AA-II combined). Staying within this limit of maximum aristolochic acid content would be possible if those species with low levels of aristolochic acid were to be used. In granules the content could be higher with reduced maximum dosage, analogous to the drug-extract rate.

The 50% tumour chance occurring in 1 in 10,000 cases – during a lifetime – corresponds to the risk of death by cancer that is expected every year from the maximum permissible radiation dose of 1mSV to which the nuclear facilities can expose the normal German population [17] (calculated with the assumption of a linear dosage-effect rate and using the data provided by the International Commission on Radiological Protection (ICRP), which might be grossly underestimating the risk [18]).
 

Conclusion:

The cancer risk can be reduced to a minimal and acceptable value by guaranteeing the quality of xi xin herbs and herbal extracts, and by reducing the allowed length of administration. This entails verification of identity and testing for aristolochic acid with adequate methodology, as there are 30 different Asarum species and 4 sub-species in China and as adulterations are common [3]. Banning all use of Asarum is disproportionate and a significant loss of treatment options in Chinese herbal medicine.

Axel Wiebrecht, M.D.
General medicine, naturopathy, Chinese Medicine
Bundesallee 141
D-12161 Berlin
Tel. +49 (0)30 8591067
This email address is being protected from spambots. You need JavaScript enabled to view it.

Literature:

  1. Pharmacopoeia of the People's Republic of China. Vol. I. Beijing: People's Medical Publishing House, 2005
  2. Drew AK, Whyte IM, Bensoussan A, et al. Chinese herbal medicine database: monograph on Herba Asari, "Xi Xin". Clin Toxicol 2002;40:169-172
  3. Bensky D, Clavey S and Stöger E. Chinese Herbal Medicine. Materia Medica. 3th ed. Seattle: Eastland Press, 2004
  4. Chen C, Spriano D, Lehmann T, et al. Reduction of safrole and methyleugenol in Asari radix et rhizoma by decoction. Forsch Komplementmed 2009;16:162-6
  5. Wiebrecht A. Über die Aristolochia-Nephropathie. Dt Zschr Akupunktur 2000;43:187-197
  6. Nortier JL, Martinez M-CM, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). New Engl J Med 2000;342:1686-92
  7. Government of Hong Kong, Department of Health. Management of aristolochic acid (AA) containing herbs and products, 11 June 2004,http://www.cmchk.org.hk/pcm/news/AA_CMTraders_e.pdf
  8. Hashimoto K, Higuchi M, Makino B, et al. Quantitative analysis of aristolochic acids, toxic compounds, contained in some medical plants. J Ethnopharmacol 1999;64:185-9
  9. Jong TT, Lee MR, Hsiao SS, et al. Analysis of aristolochic acid in nine sources of Xixin, a traditional Chinese medicine, by liquid chromatography/atmospheric pressure chemical ionization/tandem mass pectrometry. J Pharm Biomed Anal 2003;33:831-7
  10. Schaneberg BT, Khan IA. Analysis of products suspected of containing Aristolochia or Asarum species. J Ethnopharmacol 2004;94:245-9
  11. Jiang X, Wang ZM, You LS, et al. [Determination of aristolochic acid A in Radix Aristolochiae and Herba Asari by RP-HPLC] (Chinese). Zhongguo Zhong Yao Za Zhi 2004;29:408-10
  12. Zhao ZZ, Liang ZT, Jiang ZH, et al. Comparative study on the aristolochic acid I content of Herba Asari for safe use. Phytomedicine 2008;15:741-8
  13. BfArM. Aristolochiaceaehaltige Arzneimittel, die unter Verwendung von Pflanzen der Gattung Asarum hergestellt werden: Das BfArM ordnet den Widerruf der Zulassung an. Bescheid vom 22.07.2010: http://www.bfarm.de/cae/servlet/contentblob/1207042/publicationFile/9260..., date accessed 2010 Sep 1, 2010
  14. N.N. Hormone nach den Wechseljahren: der Skandal setzt sich fort. Arzneitelegramm 2002;33:81-3
  15. N. N. Blasenkrebs unter Pioglitazon (Actos u.a.). Arzneitelegramm 2010;41:108
  16. Kvaavik E, Batty GD, Ursin G, et al. Influence of individual and combined health behaviors on total and cause-specific mortality in men and women: the United Kingdom health and lifestyle survey. Arch Intern Med 2010;170:711-8
  17. Bundesministerium der Justiz. Verordnung über den Schutz vor Schäden durch ionisierende Strahlen, 2008
  18. Schmitz-Feuerhake I. Übersicht zu den Langzeitfolgen von chronischer Niedrigdosisbestrahlung. Strahlentelex 2006;20(460-461):1-5

Table 1:

species part extr. orign

AAI

[μg/g]

AAII

[μg/g]

study

Asarum sieboldii

radix(?)

ME

Japan

< 1

< 1

Hashimoto 1999

Asarum sieboldii

radix(?)

ME

Japan

< 1

< 1

 

Asarum heterotropoides var. mandshuricum

radix(?)

ME

China, Liaoning

< 1

< 1

 

Asarum heterotropoides var. mandshuricum

radix(?)

ME

China, Jilin

< 1

< 1

 

Asarum heterotropoides var. mandshuricum

radix(?)

ME

North Korea

< 1

< 1

 

Asarum heterotropoides var. mandshuricum

radix(?)

ME

Liaoning

< 1

< 1

 

Asarum sieboldii var. seoulense

radix(?)

ME

Korea

< 1

< 1

 
             

Asarum heterotropoides var. mandshuricum

herba(?)

MEc

China

42.2

neg.

Jong 2003

Asarum crispulatum (=alternate species)

herba(?)

MEc

China

3376.9

neg.

 

Asarum sieboldii

herba(?)

MEc

China

3.3

neg.

 

Asarum fukienense (=adulterant)

herba(?)

MEc

China

16.6

neg.

 

Asarum fukienense (=adulterant)

herba(?)

MEh

China

11.7

neg.

 
             

Asarum sieboldii

herba(?)

ME

China

neg.

neg.

Schaneberg 2004

             

Asarum heterotropoides var. mandshuricum

herba

ME

Jilin

50.69

 

Jiang 2004

Asarum sieboldii

herba

ME

Jilin

71.06

   

Asarum heterotropoides var. mandshuricum

herba

ME

Jilin

351.1

   

Asarum heterotropoides var. mandshuricum

herba

ME

Liaoning

26.47

   

Asarum sieboldii

herba

ME

Liaoning

145.0

   

Asarum heterotropoides var. mandshuricum

herba

ME

Liaoning

neg.

   
             

Asarum sieboldii var. seoulense (A)

radix

ME

Hong Kong

0.19

 

Zhao 2008

Asarum sieboldii var. seoulense (A)

radix

WE

Hong Kong

0.04

   

Asarum heterotropoides var. mandshuricum (B)

herba

ME

Hong Kong

11.91

   

Asarum heterotropoides var. mandshuricum (B)

herba

WE

Hong Kong

0.34

   

Asarum heterotropoides var. mandshuricum (B)

planta tota

ME

Hong Kong

5.30

   

Asarum heterotropoides var. mandshuricum (B)

planta tota

WE

Hong Kong

0.25

   

Asarum heterotropoides var. mandshuricum (B)

radix

ME

Hong Kong

2.16

   

Asarum heterotropoides var. mandshuricum (B)

radix

WE

Hong Kong

0.15

   

Asarum heterotropoides var. mandshuricum (C)

herba

ME

Hong Kong

6.14

   

Asarum heterotropoides var. mandshuricum (C)

herba

WE

Hong Kong

0.31

   

Asarum heterotropoides var. mandshuricum (C)

planta tota

ME

Hong Kong

2.21

   

Asarum heterotropoides var. mandshuricum (C)

radix

ME

Hong Kong

0.93

   

Asarum heterotropoides var. mandshuricum (C)

radix

WE

Hong Kong

0.05

   

Asarum heterotropoides var. mandshuricum (C)

planta tota

WE

Hong Kong

0.09

   

Table 1: Content of aristolochic acid-I (AA-I) and aristolochic acid-II (AA-II) in different species of Asarum, different parts of plant and different modes of extraction. Officinal species with the part radix are marked green, other parts yellow, and non-officinal species pink. Contents of watery extraction of the officinal species are in bold, they equate to a content which is expected by a decoction. ME = methanolic extraction, MEc = extracted with cold methanol, MEh = extracted with hot methanol, WE = watery extraction

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