MISIDENTIFICATION, SUBSTITUTION, OR CONTAMINATION

II. MISIDENTIFICATION, SUBSTITUTION, OR CONTAMINATION

Misidentification or mislabeling of herbs may result in unexpected adverse clinical effects. One problem in the identification of herbal ingredients is that the plant materials can be named in four different ways—the common English name, the transliterated name, the Latinized pharmaceutical name, and the scientific name. The Chinese names of different substances are sometimes similar and a raw material may have several Chinese proprietary names. It is desirable that plants are referred to by their binomial Latin names for genus and species; misidentification is more likely to occur when other names are used. Furthermore, plant material can be misidentified when wild plants are harvested or at the time of the manufacturer’s bulk purchase.

A. Guijiu One tragic example occurred in Hong Kong when the toxic herb guijiu, which

is derived from the root and rhizome of Podophyllum hexandrum (P. emodi), was found as an adulterant of the herb longdancao (Gentiana rigescens) in 1989, which led to two cases of serious and permanent neuropathy and encephalopathy (11). Subsequent investigations revealed that the adultera- tion was made by the supplier in mainland China, but no one in the supply chain noticed the error until the occurrence of the adverse event. This same toxic herb also appeared as a contaminant in samples of the herb weilingxian

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(Clemetis sp.) resulting in miniepidemics of three and nine cases of neurop- athy in 1995 and 1996, respectively (12).

The products of the rootstock of P. emodi are generally too toxic to be used other than for external application. The toxic constituent of guijiu is podophyllotoxin, which is predominantly a neurotoxin but it can also damage the liver, intestine, and pancreas. It appears to inhibit protein synthesis and mitosis (13). The symptoms of toxicity include nausea, vomiting, diarrhea, and abdominal pain and in severe cases neuropathy and encephalopathy may develop and result in permanent neurological damage. Abnormal liver function tests, thrombocytopenia, and leukopenia may also occur. Bajiaolian, the root of Dysosma pleianthum, one of the species in the mayapple family, has been widely used in mainland China and Taiwan as a TCM remedy for snakebites, general weakness, poisoning, condyloma acuminatum, lymph- adenopathy, and certain tumors. Toxic effects have resulted from accidental ingestion or topical application and some cases occurred when some people took what they thought were therapeutic doses, resulting in podophyllotoxin toxicity (14).

B. Anticholinergic Toxicity Likewise, the erroneous dispensing of yangjinhua (the flowers of Datura metel

L.) instead of the prescribed lingxiaohua (flower of Campsis grandiflora) has led to four cases of drowsiness or acute confusion due to the anticholinergic effects of this herb (15). Herbs such as yangjinhua or naoyanghua (flowers of Rhododendron molle ) may be used for upper-respiratory problems such as chronic bronchitis or asthma or various painful conditions but in excessive dosage they may result in an acute confusional state with signs of central nervous system and peripheral anticholinergic toxicity (16). The typical features include confusion or coma, fever, tachycardia, flushed dry skin, dilated pupils, dry mouth, and urinary retention. The herbs contain scopol- amine, hyoscyamine, and atropine. Datura species were the most common cause of plant poisonings in a series of TCM poisoning cases from Taiwan (17).

C. Aristolochic Acid Another case of erroneous substitution occurred in Belgium when guang-

fangji (Aristolochia fangchi) was used instead of fangji (Stephania tetrandra) in

a combined slimming regimen that included some Western medications (18).

A. fangchi contains the nephrotoxin aristolochic acid; this resulted in a number of cases of renal toxicity with rapidly progressive fibrosing interstitial nephritis and some patients developed irreversible end-stage renal failure or carcinoma in the urinary tract (19,20). The toxic effect could have been potentiated by the other drugs used such as acetazolamide (18,19).

Adverse Effects of CHM 887

D. Chansu Chansu, or toad cake, is made from the dried venom of the toad Bufo bufo

gargarizans or B. melanostictus. This is prepared from the skin and venom glands of the toad. It is stored in a disc shape of dry material, which has been mistaken for another innocuous material prepared from the hide of the ass. Chansu is used for its anti-inflammatory analgesic and anesthetic properties. It contains bufotoxins, which have a digoxin-like effect, and excessive doses may cause cardiac arrhythmias that may be fatal. Chansu was the most common cause of fatal toxicity due to TCM in a series reported from Taiwan where over 14 years there were 7 deaths related to this of a total of 43 (17). It is also found in the proprietary Chinese medicine lushenwan, which is a popular remedy for upper-respiratory symptoms or used as a topical prep- aration for skin infections. Overdosage of lushenwan pills can cause cardiac glycoside toxicity in children and topical applications may cause local skin inflammation.

E. Ginseng In TCM ginseng is considered a panacea and has been attributed with many

activities, including as an adaptogen, antistress, antifatigue, anticancer, antiaging, immunomodulating, as well as a performance enhancer, and aphrodisiac, although scientific evidence to support such claims is limited (21–23). Ginseng is generally regarded as safe but a number of adverse effects have been reported with ginseng products including central-nervous-system excitatory effects, hypertension, insomnia, tachycardia, and hormonal effects resulting from corticosteroid-, estrogen-, or androgen-like actions (21,22,24– 26). Some of the adverse effects attributed to ginseng preparations may have been due to misidentification or substitution and there is a great variation in the quality of different products (27). Ginseng historically refers to the products from the Panax species. Chinese and Korean ginsengs come from Panax ginseng

C.A. Meyer whereas American ginseng is prepared from Panax quinquefolius L. These have different combinations of chemical components and different uses but all the Panax species products should contain ginsenosides, the steroidal saponins with a 4-trans-ring steroid skeleton that are associated with pharmacological activities and are used as markers of quality control (28).

Siberian ginseng is prepared from the roots of Eleutherococcus sentico- sus , which is from the same family (Araliaceae) but a different genus than the Panax species. It does not contain ginsenosides but has eleutherosides, which are used as quality control markers for these products. These are chemically related to cardiac glycosides and may interact with some digoxin assays. This may have been responsible for a case of apparent elevation of serum digoxin

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levels with no signs of toxicity when Siberian ginseng and digoxin were taken together (29) although it was also suggested that the herb may have been misidentified (30). Another case involving neonatal androgenization associ- ated with maternal use of Siberian ginseng (31) appears to have been due to misidentification of the herb involved as it was later identified as Chinese silk vine (Periploca sepium) (24). Studies in rats showed Siberian ginseng was not associated with androgenicity (32).

Estrogenic effects have been attributed to ginseng in both oral and topical preparations resulting in postmenopausal bleeding (25,33) or mastal- gia (34) but the source and purity of the products involved were not specified. Likewise, the ‘‘ginseng abuse syndrome,’’ which involved elevation of mood, hypertension, nervousness, sleeplessness, skin eruptions, diarrhea, and ede- ma, was attributed to long-term usage of ginseng with other stimulants such as coffee but the origin, composition, and dosages of the products involved were not specified (35).

Interactions with other drugs have been reported with ginseng therapy. Ginseng has been reported to interact with phenelzine and other MAOIs to have a stimulatory effect on the central nervous system inducing headache and tremor (36,37) An interaction with warfarin was apparent as the International Normalised Ratio (INR) clotting index fell from 3.1 to 1.5 while the combination was taken and normalized after withdrawal of the ginseng (38). This interaction has not been confirmed by other studies and one study in rats showed no significant impact of ginseng on the pharmacokinetics or pharmacodynamics of warfarin given in single or multiple doses (39). In healthy human subjects P. ginseng acute or 28-day supplementation had no significant effect on the activity of CYP1A2, CYP2D6, CYP2E1, or CYP3A4 measured by a cocktail of probe drugs (40). Studies in rabbit platelets showed that some components of ginseng had antiplatelet activity (41).