Pinelliae Rhizoma, ban xia

Pinelliae Rhizoma (ban xia) plays an important role in Chinese medicine. The unprocessed herb is classified as toxic; therefore, only the processed form may be used for internal admi­ni­stration. This raises the question of whether the properly processed herbal medicine, Pinelliae Rhizoma Praeparatum (zhi ban xia), also poses a risk when administered internally.

Unprocessed Pinelliae Rhizoma (sheng ban xia)

Unprocessed Pinelliae Rhizoma (sheng ban xia) can cause intoxication at doses as low as 0.1–0.8 g. Symptoms develop within 30 minutes to 2 hours after ingestion and include a burning sensation in the mouth, numbness and swelling of the mouth and tongue, mucosal erosions, salivation, difficulty opening the mouth, a sensation of dryness in the throat, hoarseness, laryngospasm, dysphagia, vomiting, and diarrhea. Ingestion of an excessive dose could lead to hepatic and renal injury, along with neurological manifestations such as dizziness and limb paresis, potentially progressing to coma and respiratory arrest, which may result in death by asphyxiation. In children, the herb may impair intellectual development and cause irrever­sible neurological damage [1, 2]. Potential cardiotoxic effects include palpitations, cardiac arrhythmias (tachycardia, nodal escape rhythm, atrial flutter, and atrial fibrillation), and heart failure [3].

The mucosal irritant effects of the herb are attributed to the sharp calcium oxalate crystals it contains. A study of Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (Jiang Ban Xia) demonstrated that processing does not reduce the calcium oxalate content but does cause the sharp needle-shaped crystals to aggregate into bundles containing blunter needles [4]. The constituents responsible for the full spectrum of toxic effects have not yet been adequa­tely elucidated.

Processed Pinelliae Rhizoma (zhi ban xia)

The three main processing methods are as follows:

• Pinelliae Rhizoma Praeparatum (fa ban xia): This is the standard processing method. The herb is soaked for several days in a solution of licorice and lime at a pH above 12. Fa ban xia is particularly effective in addressing cold-phlegm and dampness-phlegm.
• Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (jiang ban xia): In this method, the herb is boiled in a solution containing ginger and Alumen (bai fan). Jiang ban xia acts primarily on the middle burner, transforms phlegm, directs rebellious qi downward, and alleviates vomiting.
• Pinelliae Rhizoma Praeparatum cum Alumine (qing ban xia): This preparation is produced by boiling the herb in an 8% Alumen solution or by soaking it for an extended period. Qing ban xia primarily dries dampness and transforms phlegm [5].

Case Reports

How should the tolerability of processed Pinelliae Rhizoma (zhi ban xia) be assessed? While numerous case reports from China describe poisoning caused by the unprocessed herb, some involving high doses, we identified only three case reports from China involving pro­cessed or purportedly processed Pinelliae Rhizoma.

In the first case, a 45-year-old woman, herself a physician, took 15 g of ‘zhi ban xia’ as part of a modified combination of the formulas xiang sha ping wei san and er chen tang. The follo­wing day, she experienced itching, swelling, and pain in the throat, a burning sensation, and hoarseness. Her pre-existing epigastric discomfort worsened, and she developed loss of appetite and nausea. The pharmacy confirmed the authenticity of the herbal medicines. Subsequent analysis provided evidence suggesting that the herb had been inadequately processed: A test solution prepared from the outer layer of the herb caused no symptoms, whereas a solution prepared from the inner layer did [6]. Furthermore, the standard dosage range for zhi ban xia (3–9 g) had been exceeded.

In another case, a 63-year-old woman took a decoction containing fa ban xia 9 g, zhi ma huang 9 g, gui zhi 9 g, xi xin 3 g, wu wei zi 10 g, chuan bei mu 10 g, zi su zi 20 g, bai jie zi 20 g, and jie geng 10 g. Two hours after taking the first dose, she developed muscle twitching in the extremities, hallucinations, agitation, and delirium. Upon admission to hospital a further six hours later, she was comatose and delirious, with a pulse rate of 124 beats/min, persis­tent muscle twitching, pathologically exaggerated reflexes, and moist crackles on lung aus­cultation. One hour later, she regained consciousness, and the muscle twitching subsided [7]. In this case, the doses of Sinapis Semen (bai jie zi; standard dose 3–9 g) and Perillae Fructus (zi su zi; standard dose 3–10 g) were excessive. The report provides no information on whe­ther the patient had taken any other medications, including conventional pharmaceu­ti­cals.

In the third case, a 39-year-old woman had ingested more than 20 packets of qing ban xia, each containing 2 g. On admission to hospital, she was deeply comatose, with pinpoint pupils that reacted sluggishly to light, a blood pressure of 175/85 mmHg, reduced muscle tone, and diminished reflexes. She was successfully treated with gastric lavage, venovenous hemofiltra­tion, and hemoperfusion [8]. The report provides no explanation for how she came to ingest more than 40 g of qing ban xia, but it can be assumed that this was not the result of a medi­cal prescription.

Case 1 involved relatively mild symptoms following an overdose of apparently inadequately processed Pinelliae Rhizoma. It does not indicate a risk associated with properly processed zhi ban xia when used within the recommended dosage range. Case 3 clearly involved an excessive overdose and likewise provides no basis for inferring a risk under normal condi­tions.

This leaves case 2, which involved reportedly processed Pinelliae Rhizoma (fa ban xia) at a dose that remained within the standard dosage range. Since this is the only case report we could identify under these conditions, and given the severity of the symptoms, the adequacy of processing must be questioned, particularly since no verification of proper processing was performed. The symptoms are not entirely typical of those reported following exposure to unprocessed Pinelliae Rhizoma. Whether the excessive doses of two other herbal medicines contributed to the clinical presentation could not be determined.

The CTCA has received no reports of suspected adverse drug reactions in which Pinelliae Rhizo­­ma may have played a causal role, nor has the CTCA become aware of any such cases in Europe.

Potential Incompatibilities

According to the traditional rule of the 18 Incompatibilities, Pinellia is incompatible with all Aconitum herbal medicines. The validity of this potential interaction risk has been widely debated [9]. Many renowned physicians, including Zhang Zhongjing, Li Shizhen, and Sun Simiao, described formulas combining fu zi(Aconiti Radix Lateralis Praeparata) with ban xia. This combination is also used relatively frequently in modern clinical practice [9].

We identified three case reports describing intoxication associated with the concomitant use of Pinelliae Rhizoma and Aconitum medicines. In one case, a decoction was administered that contained, among other ingredients, 8 g of zhi ban xia, 10 g of zhi chuan wu (Aconiti Radix Praeparata), 5 g of zhi cao wu (Aconiti Kusnezoffii Radix Praeparata), and 8 g of chuan bei mu (Fritillariae Cirrhosae Bulbus). Fritillariae Cirrhosae Bulbus is traditionally also con­sidered incompatible with Aconitum medicines. One and a half hours after taking the first dose, a 44-year-old man developed severe signs of intoxication, including dyspnea, limb spasms, paralysis, and impaired consciousness [10]. As both Aconitum medicines were administered at substantially excessive doses, this case can hardly be cited as evidence of an interaction risk under normal conditions. The neurological symptoms are more consistent with intoxication caused by unprocessed Pinellia than with Aconitum overdose. It is therefore worth considering whether the Pinellia used had been adequately processed and whether its effects may have been further exacerbated by Aconitum. Since proper processing cannot be verified, this question remains unresolved.

In another case, 6 g of qing ban xia was administered together with 6 g each of Aconiti Radix Praeparata and Aconiti Kusnezoffii Radix Praeparata. Within just 10 minutes, a 35-year-old woman developed signs of intoxication characteristic of Aconitum poisoning, including atrial fibrillation and circulatory shock [11]. As the Aconitum herbal medicines were administered at substantially excessive doses, the outcome can be explained without invoking a drug inte­raction.

In the third case, a 30-year-old patient took a decoction containing 10 g of ban xia and 10 g of fu zi (Aconiti Radix Lateralis Praeparata). Signs of intoxication characteristic of Aconitum poisoning developed, including bradycardia and a nodal escape rhythm [12]. In this case, no information was provided regarding whether the ban xia had been processed. Consequently, this report does not provide reliable evidence of an interaction involving processed ban xia.

Studies on Interactions

Zhang Ling et al. conducted a study on mice to investigate the extent to which the acute toxicity of an ethanol extract of unprocessed Aconiti Kusnezoffii Radix was affected by ethanol extracts of fa ban xia, Trichosanthis Fructus (gua lou), and Bletillae Rhizoma (bai ji). While the toxicity increased following administration of the Trichosanthes and Bletilla extracts, it decreased with increasing doses of the fa ban xia extract [13]. Other animal studies reported increased toxicity with the combination of Aconitum and Pinellia [9, 14], whereas an in vitro study suggested an increase in toxicity only with unprocessed Pinelliae Rhizoma [15].

A more recent review identified 1,588 clinical studies or case series in which Aconitum and Pinellia appeared together in herbal formulas. Only 79 provided specific information on adverse effects. Pinellia and fu zi were the most frequently co-administered substances, at doses of 10 g and 15 g, respectively, although doses of up to 30 g of each substance were also reported. Gastrointestinal adverse effects were reported most frequently, whereas cardiac symptoms were uncommon; in particular, no cardiac arrhythmias were reported. Neurological effects of non-severe intensity were reported more frequently. Overall, the information provided in these studies was too imprecise or incomplete to permit reliable conclusions regarding the safety of the Aconitum–Pinellia combination, particularly because the other ingredients in the formulas would also need to be considered when evaluating the reported adverse effects [16].

Conclusion

Provided that the medicinal substance meets appropriate quality standards and is admi­nistered at the recommended dosage, serious adverse effects from Pinelliae Rhizoma Praeparatum (zhi ban xia) are not expected. However, allergic reactions and mild gastroin­testinal complaints may occur [17]. The standard dosage of 3–9 g should be strictly adhered to and appropriately reduced in children, older adults, and debilitated patients. Pinelliae Rhizoma Praeparatum is contraindicated during pregnancy [18]. The herbal medi­cine should be obtained from a reputable supplier. Although the combination with Aconitum medicines are unlikely to pose an increased safety risk, a cautious dosing regimen should nevertheless be adopted as a precaution.

References

1. Yu TT, Li WP and Ding ZS. [Understanding the application and toxicity of Pinelliae Rhizoma] (Chinese). Xiandai Zhongyao Yanjiu Yu Shijian [Chin Med J Res Prac] 2012;26:79-82

2. Government of the Hong Kong Special Administrative Region, Chinese Medicine Regulatory Office. [A reference book for Chinese medicines which had been reported as adverse events in Hong Kong] (Chinese). https://www.cmro.gov.hk/html/b5/useful_information/public_health/ publication/AdverseEventsIndex.html, 2013 (last amendment 2020)

3. Chen L, Zhang HZ and Li GX. [Standardized research on clinical symptoms of ADRs involving the circulatory system] (Chinese). Liaoning Zhong Yiyao Daxue Xuebao [Journal of Liaoning University of TCM] 2015;17:66-69

4. Yu Y, Huang YM, Wu ZJ, et al. [A study on the changes of calcium oxalate needle crystals in toxic Chinese herbs of the Araceae family before and after processing] (Chinese). Zhong Yao Cai [Journal of Chinese Medicinal Materials] 2014;37:1765-1767

5. Hu CJ, Nögel R, Hummelsberger J and Engelhardt U. Paozhi: Die Aufbereitung chinesischer Arzneimittel. Berlin: Springer, 2018

6. Li Y. [Cause analysis of one case of poisoning by prepared Pinelliae Rhizoma] (Chinese). Chuanbei Yixue Yuan Xuebao [Journal of North Sichuan Medical College] 1999;14:76

7. He TG. [A case of processed Pinelliae Rhizoma poisoning] (Chinese). Zhongguo Xiangcun Yisheng Zazhi [Journal of Chinese Rural Physician] 2008;24:111

8. Wang XL, Chen X, Ran F, et al. [Successful rescue of a patient with coma due to Qingbanxia poisoning: a case report] (Chinese). Zhongguo Zhong Xiyi Jiehe Jijiu Zazhi [Chin J TCM WM Crit Care] 2014;21:472

9. Du M. [The application of Fuzi and Banxia] (Chinese). Xiandai Zhong Yiyao [Modern Traditional Chinese Medicine] 2008;28:1-2,16

10. Tang YR. [One case report of adverse reaction to a formula containing Aconiti Radix, Aconiti kusnezoffii Radix, Fritillariae cirrhosae Bulbus, and Pinelliae Rhizoma] (Chinese). Zhongguo Zhongyi Gu Shan Ke Zazhi [Chinese Journal of Traditional Medical Traumatology & Orthopedics] 1991;7:43-44

11. Yang YJ. [Analysis of a case of poisoning caused by Aconite combined with Pinelliae Rhizoma] (Chinese). Gansu Zhongyi [Gansu Journal of TCM] 1999;12:12

12. Guo XJ, Liu AS and Chu TY. [Poisoning by incompatibility of Banxia and Fuzi: report of 2 cases] (Chinese). Shandong Yiyao [Shandong Medical Journal] 2004;44:75

13. Zhang L, Liu CA, Li WH, et al. [Acute toxicity study on the combination of Aconiti Kusnezoffii Radix with Trichosanthis Fructus, Bletillae Rhizoma and Pinelliae Rhizoma] (Chinese). Shizhen Guoyi Guoyao [Lishizhen Medicine and Materia Medica Research] 2014;25:2616-2618

14. Zhang ZZ, Liu QW, Zhu HN, et al. [Experimental study on the '18 compatibilities' of Chinese traditional medicine--acute toxicity of Aconitum carmichaeli and Pinellia ternata] (Chinese). Zhongyao Tongbao [Bull Chin Materia Medica] 1983;8:33-34

15. Liu WL, Song FR, Liu ZQ and Liu SY. [A chemical study on the incompatibility of Radix Aconiti and Pinelliae Tuber] (Chinese). Huaxue Tongbao [Chemistry] 2008;71:435-438

16. Cao C, Liao WY, Zhang JW, et al. [Adverse reaction analysis of clinical use of Pinellia and Aconitum carmichaeli antagonistic combination based on the literature] (Chinese). Zhongyi Zazhi [J TCM] 2025;66:955-962

17. Zhao JY. [Summary of adverse reactions of traditional Chinese medicines and its preparations in  the recent 10 years] (Chinese). Yunnan Zhongyi Zazhi [Yunnan Journal of TCM] 1991;12:28-31

18. Wiebrecht A. Letter to the Editor regarding: Behandlung der (Hyper-)Emesis gravidarum mit Chinesischer Medizin. Chinesische Medizin 2019;34:193-195

Aconiti Radix cocta (praeparata) (zhi chuan wu), Aconiti lateralis Radix praeparata (fu zi) and Aconiti kusnezoffi Radix cocta (praeparata) (zhi cao wu) are essential herbs in Chinese Medicine (TCM). All Aconitum species are highly toxic, drugs derived from them require adequate processing. Inadequate processing or overdoses, often under „folk medicine“ conditions [1],such as Aconitum tubers being consumed as a food, sometimes in vast quantities [2], has led to many deaths in China and Hong Kong - here particularly during the period under British rule with no regulation of Chinese Medicine.

Aconiti Radix cocta (praeparata) (zhi chuan wu), Aconiti lateralis Radix praeparata (fu zi) and Aconiti kusnezoffi Radix cocta (praeparata) (zhi cao wu) are essential herbs in Chinese Medicine (TCM). Aconiti coreani Radix praeparata (zhi guan bai fu) also plays a role. These species rank among the highly toxic drugs in Chinese Medicine and have been responsible for many deaths in China and Hong Kong - here particularly during the period under British rule with no regulation of Chinese Medicine. These cases, however, can largely be traced back to misuse, such as inadequate processing or overdoses, often under „folk medicine“ conditions [1]. Aconitum tubers are also consumed in southern China as a food, sometimes in vast quantities, with corresponding outcomes [2].  

The various Aconitum species have a long history, spanning many countries, from use as arrow poisons, to agents of murder and suicide, to medicinal applications which also include incidences of poisoning. Extractum Aconiti, later the pure substance aconitine, was listed in the German Pharmacopoeia up until 1948. Unlike in European medicine, the Chinese knew as early as 1800 years ago to detoxify the drug, without affecting its therapeutic impact. 

The critical toxic alkaloids of the Aconitum herbs are aconitine, mesaconitine and hypaconitine. The first two are of similar toxicity, while the latter is approximately only one fifth as toxic. For humans approximately 1.5 to 6 mg of aconitine are lethal [3]. These compounds are diester diterpenoid alkaloids. Through hydrolysis, acetic acid is separated, producing the substances benzoylaconine, benzoylmesaconine and/or benzoylhypaconine which have approximately one 200th of the original toxicity [4]. A further process of hydrolysis produces the substances aconine, mesaconine and hypaconine, whose toxicity has in turn been reduced by the same factor. Hydrolysis is mainly carried out through long soaking in water or a saline solution, followed by heating in this liquid and/or steaming. The processed drugs in animal tests (LD50 for mice) are roughly one 200th as toxic as the raw drugs [5]. 

Symptoms of poisoning

The first symptom of an overdose of Aconitum is paresthesia of the tongue, usually described as a burning sensation. This should be taken as a warning to check the quality of the drug and its dosage and/or to reduce the dose. In the later stages of poisoning paresthesia can spread to the whole body, and dizziness, nausea and vomiting may occur, also stomach pain and diarrhea. Serious side effects of cardiac nature include palpitations, hypotension, chest pain and arrhythmias (heart block, ventricular tachycardia, ventricular fibrillation), which are the most prevalent causes when death occurs. Neurological effects include muscle weakness, paralysis and impaired consciousness. For those who survive intoxication, recovery sets in after approximately 30 hours, with no lasting harm. There is no known definitively effective drug treatment for the arrhythmias. 

Sensitivity to poisoning is generally very different intraindividually, and this also applies to the Aconitum herbs. According to case reports a 59 year-old woman died of ventricular fibrillation after taking 5 daily doses of 10g Aconiti kusnezoffii Radix praeparata (zhi cao wu) [6]; on the other hand a 59 year-old woman survived after taking unprocessed Aconiti Radix plus Aconiti Kusnezoffii Radix, in total 50g within 2 or 3 days, with symptoms only occuring after the 3rd dose [7]. Of course, the type of pretreatment and quality of the drugs play a role.

With adequate processing of the Aconitum herbs, as is customary in Europe, with appropriate dosage and adherence to contraindications, no serious side effects are to be expected. Typical values for the diester diterpenoid alkaloids in Europe are very low or below the detection limit. The Chinese Pharmacopoeia allows reasonably high values of 0.020% (fuzi, equal 200 µg/g) and 0,040% (chuan wu and cao wu, equal 400 µg/g), respectively. Should a medicine fully utilize this range and be administered in excessive doses as part of the Fire School, this may present a serious risk, even though to date no such cases are known in Europe. 

In Europe, only one single case of Aconitum poisoning caused by a (presumably) Chinese remedy has been documented: It concerns the accidental peroral intake of a product intended for skin application by a Chinese patient in London. Aconitine intake was estimated at 1 to 5mg; the patient survived the intoxication involving ventricular fibrillation [8]. The Japanese Pharmacopoeia specifies a maximal total amount of 450 µg for all diester alkaloids per g Aconiti Radix (0.045%) [9], which appears to be a sufficiently safe value. In the course of a clinical study in Japan an Aconitum extract with a total diester alkaloid content of 86 µg/g was administered in a dose of up to 6g, together with other medicines. Among the 593 patients there were only 5 cases of mild side effects [10]. 

Conclusion

Aconitum drugs should only be obtained from reliable sources, and the maximal doses, contraindications and precautions heeded (see below). Should side effects such as paresthesia of the tongue or nausea occur, the quality of the drugs and the dosage should be checked. In case of doubt, test results for diterpenoid alkaloids should be requested from the supplier. Co-medication of Aconitum herbs with Evodiae Fructus (wu zhu yu) or digitalis must be avoided because these use a similar pharmacological principle (Na⁺/K⁺ pump); antiarrhythmic drugs may cause hazardous interactions, too. Under adherence to these provisions, the Aconitum herbs - being essential herbs in Chinese medicine - present no significant risk.

Cautions for the use of Aconitum herbs

Maximal doses

Aconiti lateralis Radix praeparata (fu zi), 15g
Aconiti Radix cocta (praeparata) (zhi chuan wu), 3g
Aconiti kusnezoffi Radix cocta (praeparata) (zhi cao wu), 3g

Contraindications

Heart conditions (heart failure, coronary heart disease, cardiac arrhythmias), pregnancy, lactation, co-medication with Evodiae Fructus (wu zhu yu), digitalis or antiarrhythmic drugs

Caution with

Children, elderly patients, yin deficiency, yang excess, heat excess, co-medication with Ephedrae Herba (ma huang), Periplocae Cortex (xiang jia pi) or Fossilia Ossis Mastodi (long gu)

Sources

1. Chan TY. Incidence and causes of Aconitum alkaloid poisoning in Hong Kong from 1989 to 2010. Phytother Res 2015;29:1107-11
2. Chan TY. Aconitum alkaloid poisoning related to the culinary uses of aconite roots. Toxins 2014;6:2605-11
3. Blaschek W, Ebel S, Hackenthal E, et al. Aconitum. Hagers Enzyklopädie der Arzneistoffe und Drogen. 6. Aufl. Bd. 1. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 2007:257-278
4. Sato H, Yamada C, Konno C, et al. Pharmacological actions of aconitine alkaloids. Tohoku J Exp Med 1979;128:175-87
5. Hikino H, Yamada C, Nakamura K, et al. [Change of alkaloid composition and acute toxicity of Aconitum roots during processing] (Japanese). Yakugaku Zasshi 1977;97:359-66
6. But PP, Tai YT and Young K. Three fatal cases of herbal aconite poisoning. Vet Hum Toxicol 1994;36:212-5
7. Lin CC, Chan TY and Deng JF. Clinical features and management of herb-induced aconitine poisoning. Ann Emerg Med 2004;43:574-9
8. Kolev ST, Leman P, Kite GC, et al. Toxicity following accidental ingestion of Aconitum containing Chinese remedy. Hum Exp Toxicol 1996;15:839-42
9. Ministry of Health Labour and Welfare. The Japanese Pharmacopoeia XVI. Edition, English Version. 2011
10. Nagasaka K, Tatsumi T, Natori M and Hikiami H. Study of Shuchi-Bushi, a powder type of Aconiti Tuber after being autoclaved, especially concerning side effects. Usage and dosage of shuchi-bushi from this study. Kampo Med 2005;56:797-800

Asari Herba, Xi xin

The Safety of Asarum – An Evaluation

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

Axel Wiebrecht

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 species. However the amounts of both AA-I and AA-II found in officinal Asarum species are mostly very small and occasionally below the limit of detection (In comparison, non-officinal Asarum crispulatum contains high amounts of aristolochic acid). Because of the aristolochic acid content, both Switzerland and Germany banned the medicinal use of Asarum in 2010. The risk tolerance chosen is extremely low when compared to that of conventional drugs or everyday hazards. A total ban of Asarum seems disproportionate.

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:

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 = water extraction

FDA prohibits Ephedra in Supplements

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

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 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.

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. 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