Interactions between preparations can be classified scientifically into two main types:

• pharmacokinetic interactions, where one agent alters the absorption, distribution or elimination of another: for example, in Western medicine, the enzyme inhibitor ketoconazole alters the elimination of drugs metabolized by the cytochrome P450 enzyme system such as terfenadine;
• pharmacodynamic interactions, where the effect of one agent augments or diminishes the effect of the other without altering the pharmacokinetics: for example, additive CNS depression with hypnotics and tricyclic antidepressants

Table 4.4: Direct toxicity resulting from self-prescribed Chinese herbal formulae.

Woo (1994) demonstrated that up to 30% of 150 commonly used CHMs affected barbiturate-induced hypnosis in animals, but caution the extrapolation to humans60. Other reports have included potentiation of hypoglycaemic effect of antidiabetics with the herbal drug karela (Momordica charantia)61 and potentiation of warfarin in rats by Dan Shen62.

Chinese language texts discussing these interactions date back to 1918, but there are few in English. With an increasing number of Chinese herbal preparations being used in combination with western pharmecuticals, both identification of new interactions and the incidence of these interactions are likely to increase.

The Australian TCM Patient Profile (Chapter 6) showed that 35% of patients consuming Chinese herbal medicine were concurrently taking pharmaceutical medications (excluding vitamins and mineral supplements).

4.6.2 Unpredictable Reactions to Chinese Herbal Medicines
(Type B adverse effects)

As with western medicines, CHM has been associated with rare, often idiosyncratic reactions. Case reports in the literature do not allow estimation of risk, and vary in the analysis of preparations and identification of the constituents of the preparations. The majority of unpredictable reactions are due to allergy.

4.6.2.1 Significant Allergic Reaction - Royal Jelly

Over the last 20 years there have been 17 reports to the Australian Drug Reaction Advisory Committee (ADRAC) of adverse effects related to the use of royal jelly, most of them allergic reactions including asthma, anaphylaxsis and rash. While most patients recover without sequelae, there have been two deaths:

• In 1993 an 11 year old girl suffered bronchospasm, diarrhoea, vomiting and cardiac arrest following a single dose of royal jelly. The ADRAC report rated the causality as `possible'.
• In 1993 a 31 year old male developed bronchospasm and died after taking royal jelly. The dose was not reported and the ADRAC rated the causality as `possible'.

Concern regarding unsatisfactory warnings on product labels was raised in relation to both incidents.

4.6.2.2 Other Unpredictable Reactions

Several authors have reported hepatic damage from the administration of CHM for skin conditions. Kane et al (1995) reported two cases of hepatitis after ingestion of a CHM for psoriasis and eczema17. The preparations were different but each contained Dictamnus dasycarpus and Paeonia suffructicosa, which were also reported in another, fatal, case of hepatitis. While the authors suggested causality, others have suggested that Paeonia suffructicosa is free of side effects15. It is unclear how rigorously the authors identified the constituents of the preparations.

Perharic et al (1995) report several cases of hepatic damage in people taking CHM for psoriasis and eczema, with a hyperbilirubinemia and rises in the liver enzymes AST and ALT up to 69.7 times normal18. While the authors could not implicate any one preparation, most contained Dictamnus dasycarpus and Paeonia spp. Duration of exposure ranged from 2 weeks to 8 months.

Other authors have also reported hepatic dysfunction and immunosuppression after the use of CHM for the treatment of skin diseases63,64.

Hepato-renal toxicity after herbal infusion52

A 61-year-old Chinese Vietnamese woman suffered severe hepatic and renal complications following the administration of a Chinese herbal tea for pain. The patient was admitted to Monash Medical Centre, Melbourne, four days after taking the preparation containing several ingredients including Ephedra spp., Panax Pseudoginseng root (a form of Ginseng), and pollens.

Severe liver and kidney failure and problems with blood clotting were evident. While analysis of the preparation showed several potentially toxic constituents including ephedrine and coumarin artefacts, there was not sufficient information to directly implicate the preparation as the cause of the illness.

The case however, highlights the potential for idiosyncratic reactions to Chinese medicine preparations. These reactions, like idiosyncratic reactions to western medications, can lead to life threatening reactions and death.

4.6.3 Failure of Good Handling and Manufacture of CHM

Problems related to handling and manufacturing processes include:

• misidentification9,47;
• lack of standardisation65;
• contamination with heavy metals/toxins20;
• inadvertent (or deliberate) substitution of other herbs45,47; and
• adulteration with western pharmaceutical products20,66.

Officials in Beijing have recently expressed concern about the substitution or adulteration of CHM, to the extent that China intended to temporarily suspend the issuing of new permits for factories producing Chinese herbal medicines pending further review67.

4.6.3.1 Misidentification

Correct identification of the plant material in CHM9 and the nomenclature used47 can also cause problems. But9 points out that there are four ways to name a herb:

• the English common name;
• transliteration of the herb name;
• the Latinised pharmaceutical name; and
• the scientific name.

This complicates interpretation of the literature. Ginseng (the common English name), for example, is also known as ren-shen, radix ginseng, and panax ginseng. It can be difficult to trace common names, transliterations and pharmaceutical names to source species, which can result in erroneous identification, and But recommends using the binomial scientific name9.

4.6.3.2 Lack of Standardisation

A variety of factors affect the constituents of medicinal plants. These include:

• genetic variation, both interspecies and intraspecies;
• environmental factors, such as climate, altitude and growing conditions;
• time of harvesting;
• part of the plant used;
• storage conditions; and
• processing treatments68.

To ensure batch-to-batch reproducibility, identification tests are required to confirm the presence of the active constituents. Where an assay method is available it should be used in addition to quantify these constituents. These constituents, if quantifiable, should meet a minimum accepted percentage identified in the literature to have pharmocological effect. Where the active constituents have not been identified, a chromotographic `fingerprint' of the plant can provide batch-to-batch comparability68. The Pharmacopoeia of the People's Republic of China69 provides standards for 522 substances from the Chinese Materia Medica. These standards are currently not compulsory in Australia.

Lack of standardisation can lead to sub-potent (and possibly super-potent) therapeutic preparations being available, and this can lead to compromise and failure of herbal treatment and may place some individuals at risk.

In 1994, Cui et al compared the ginsenoside content of 50 brands of ginseng sold in 11 countries65. Ginsenocide is a glycosylated steroid to which most of the biological activity of ginseng (Panax ginseng) has been ascribed. The concentration ranged from 1.9 - 9 %w/w in 44 of these products and 6 contained no ginsenosides. One of these six contained large amounts of ephedrine, a drug for which a Swedish athlete was accused of doping65.

4.6.3.3 Contamination

Potential contaminants of herbal medicines include micro-organisms, microbial toxins, pesticides, fumigation agents, radioactivity and heavy metals61. These contaminants have been identified by the Committee for Proprietary Medicinal Products (CPMP) of the European Community (EC) in controlling the purity of herbal medications70. The CPMP Guidelines highlight the need for good control of the starting materials and the finished product and emphasise the importance of good manufacturing practice. Potential contaminants are listed in Table 4.5.

Table 4.5: Potential contaminants that require monitoring in the quality control of herbal medicines. [Modified from De Smet61]

Cases of contamination other than with heavy metals were not cited in the literature. However, it cannot be presumed this does not occur. More probably, it has not been the focus of any extensive investigation.

No examples of contamination were noted in Australia. Cases of heavy metal toxicity have been reported in overseas jurisdictions. The reports include cadmium, lead, arsenic, mercury and thallium poisoning20,61,71,72. Table 4.6 lists contamination identified.

In Australia, there is no routine monitoring of these contaminants in imported raw Chinese medicines used by individual practitioners. The good manufacturing practice procedure for the identification of contaminants in manufactured herbal products by manufacturers approved by the Commonwealth Therapeutic Goods Administration specifies detection of micro-organisms, leaving estimation of other contaminants to the discretion of the manufacturers.

Table 4.6: Identified contamination of Chinese herbal medicine with heavy metals

4.6.3.4 Substitution of Materials Used in CHM

The overseas literature cites inadvertent or deliberate substitution of the constituents of CHM preparations. For example, cheaper substitutes such as Siberian ginseng (Eleutherococcus senticosus), American ginseng (Panax quinquefolium), or Japanese ginseng (Panax pseudo-ginseng) have been substituted for Korean or Chinese ginseng (Panax ginseng)21. Sometimes the substitute has had much greater toxicity than the original. Examples of substitution resulting in an adverse effect include:

• hepatitis with Jin Bu Huan45
• renal fibrosis due to Aristolochiae Fangchi47
• podophyllin poisoning due to Podophyllum emodi21

Table 4.7 lists reported substitutions with CHM.

Hepatitis and Jin Bu Huan

Woolf et al (1994) reported seven patients in the USA with acute hepatitis after consuming Jin Bu Huan (Lycopodium serratum), used for pain relief and insomnia45. The reaction developed after an average of 20 weeks therapy and resolved in most patients in a mean of 8 weeks. The package insert showed that the product contained 30% levo-alkaloid from Polygala chinensis, but analysis suggested a more toxic substitute74, an alkaloid from Stephania and Corydalis genera and not from Polygala45.

Table 4.7: Substitutions of Chinese herbal medicine

Interstitial renal fibrosis and aristolochic acid

More than 70 cases of renal failure following ingestion of a slimming preparation containing Chinese herbs were identified in Belgium47,50 between January 1989 and January 1994. Of these, 30 progressed to terminal renal failure50. Nephropathy is characterised by extensive interstitial fibrosis with atrophy and loss of the tubules48. There is also suspicion of increased renal malignancies in these patients75.

The preparation purported to contain Stephania tetrandra and Magnolia officinalis, but initial investigations suspected substitution of Aristolochiae fangchi for S. tenandra (Fangji) due to possible mistakes with nomenclature. The Aristolochiae spp. contain aristolochic acid, which is nephrotoxic in animals and humans76, and the features of Balkan Endemic Nephropathy, a severe renal side effect in which aristolochic acid has been suggested as a possible cause, are similar to those reported in Belgium49. The initial reports failed to detect aristolochic acid47, but more sophisticated investigations suggest that the batch of herbs labelled S. tenandra contained aristolochic acid and not tetrandrine50.

Podophyllum poisoning

There are reports of inadvertent substitution of `Gui Jiu' (Podophyllum emodi Wall) for `Long Dan Cao' (Gentiana spp.)21. This resulted in severe neurological, gastrointestinal, renal and hepatic manifestations21,73.

4.6.3.5 Adulteration with Western Pharmaceuticals

There are several reports in the literature regarding the intentional adulteration of Chinese herbal medicines with western pharmaceuticals21. The adulterants range from non-steroidal anti-inflammatory agents, corticosteroids through to sedatives such as diazepam. The only reported Australian case occurred in 1995 in Victoria and involved a cortisone steroid cream in a CHM for skin conditions, resulting in severe toxicity66. Table 4.6 identifies reported cases of adulteration of CHM.

Adulteration has made it more difficult to attribute efficacy to CHM as well as leading to severe adverse effects77,78.

Table 4.8: Western pharmaceuticals found as adulterants in Chinese herbal medicine