九龙坡区广厦城外的道路上，有市民来电反映...
Abstract
Abstract. Ernst E. (University of Exeter, Exeter, UK). Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review (Review Article). J Intern Med 2002; 252: 107–113.
The popularity of Chinese herbal medicines (CHMs) demands a critical analysis of safety issues. The aim of this systematic review is to summarize data regarding adulterations of CHMs with conventional drugs. Literature searches were carried out in six databases. Articles containing original data on adulterations were considered without language restrictions. Eighteen case reports, two case series and four analytical investigations were identified. The list of adulterants contains drugs associated with serious adverse effects like corticosteroids. In several instances, patients were seriously harmed. One report from Taiwan suggests that 24% of all samples were contaminated with at least one conventional pharmacological compound. It is concluded that adulteration of CHMs with synthetic drugs is a potentially serious problem which needs to be addressed by adequate regulatory measures.
Introduction
Chinese herbal medicines (CHMs) are becoming more and more popular in western countries [1, 2]. CHMs are widely available, not least through the internet. This popularity renders a critical assessment of their safety an urgent necessity. Whilst problems relating to the toxicity of their herbal ingredients have been repeatedly reviewed (e.g. Ref. [3]), other important safety issues have so far been neglected [4, 5]. One such topic is the possibility of adulteration of CHMs with conventional drugs. A recent report indicated that this issue could be important: of 260 `Asian' (no further details provided) patent medicines that had been collected from Californian outlets, 7% contained undeclared pharmaceuticals [6].
The following systematic review is aimed at briefly summarizing the evidence related to the adulteration of CHMs by synthetic therapeutic substances.
Method
Systematic searches on the Medline, Embase, Biosis, Amed, Cochrane Library and CISCOM databases were performed. Databases that are published in Chinese, e.g. `China Biological Medicine Database' were not consulted. The search terms used were: adulteration, adverse (effects or events), alternative medicine, Asian medicine, Chinese medicine, herb, herbal medicine, phytomedicine, safety, side-effects, toxicity and traditional medicine. Each database was searched from its inception until December 2001. Manufacturers of CHM preparations and experts in the field were asked about any published or unpublished data. The bibliographies of all papers were subsequently searched for further reports. No language restrictions were applied in the selection of articles. Selected articles were required to contain original data relating to adulteration of CHMs with conventional drugs. Such articles were considered irrespective of their design, e.g. case reports, analytical investigations, etc. Articles that did not sufficiently specify the origin of the remedy were excluded [6] (`Asian', for instance, could mean Ayurvedic, Kampo or Chinese medicine). Reports of contamination by other medicinal plants (e.g. Ref. [7]) were also excluded.
Data were extracted by the present author according to predefined criteria (see headings of Tables?1–tblr rid="t3">3 and summarized in narrative form. Reports were categorized into case reports, case series or analytical investigations. Articles that described several cases individually and in sufficient detail (e.g. Ref. [3]) were categorized as case reports and data were extracted on each case separately (Table?1).
Results
The search strategy generated 22 articles that could be included [8–29]. The vast majority of reports related to oral use of CHMs, but in five instances they related to topical application of CHMs [15, 18, 21, 28].
Case reports
Fifteen of these articles [8–22] related to case reports describing a total of 19 cases (Table?1) originating from the US [8, 14], Australia [9, 12, 13, 21, 22], UK [10, 15, 16, 18], Holland [11], Belgium [17] and New Zealand [19]. Only one report came from China [20]. Many of these case reports lack details that would be important for a rigorous evaluation. For instance, some fail to mention the exact type of CHMs causing the problem (e.g. Ref. [8]), the source of the CHMs (e.g. Refs [11, 20]), a description of the affected patient (e.g. Ref. [11]) or the clinical outcome (e.g. [10–16, 18, 19]). The adulterants cover a wide range of pharmaceuticals: aminopyrine [8, 9, 12], phenylbutazone [8, 9, 13], phenacetin [9], dexamethasone [10, 11, 16, 17], indometacin [10, 11, 17], diazepam [11, 17], hydrochlorothiazide [11, 17], hydrocortisone [14], fluocinolone acetonide [15], diclofenac [17], mefenamic acid [17], clobetasol propionate [19], phenytoin [20], methylsalicylate [21] and glibenclamide [22]. In 10 instances [12–16, 19–22], only one adulterant was identified. In all other cases, two or more adulterants per CHM were found. Children were the victims in two instances [15, 16]. In many cases, the resulting signs and symptoms were serious or even life-threatening: agranulocytosis [8, 9], Cushing's syndrome [10, 11, 16, 17], coma [20], excessive increase of INR [21] and hypoglycemia [22]. In other cases, the adulterants caused no symptoms at all and the problem was disclosed only through routine check-ups [12, 13]. In other instances again, the suspicion of adulteration was raised through the good clinical response to a CMH [14, 15, 18, 19]. Most patients made full, speedy recoveries after withdrawal of the adulterated CHM, but one death because of septic shock is also on record [8].
Case series
Two case series (Table?2) including a total of 21 patients were found [23, 24]. The adulterants included mefenamic acid, diazepam [23], prednisolone and indometacin [24]. The clinical effects were in some case serious: somnolence, massive gastrointestinal bleeding, Cushing's syndrome, diabetes, hypertension, arrhythmia. In one of these case series [24], the clinicians were alerted to the possibility of adulteration not through adverse effects but through the seemingly good clinical response caused by the adulterants.
Analytical investigations
Six articles (Table?3) related to analyses of CHMs collected in Australia [21], Japan [25, 29], US [26], Taiwan [27] and UK [28]. Perhaps the most informative and largest of these reports is the study of Huang and colleagues [27]. These authors showed that 24% of all 2609 samples collected in Taiwan were contaminated by at least one adulterant. The adulterants identified in the analytical investigations were similar to those demonstrated in case reports but several remarkable new chemical entities were also found: caffeine, acetaminophen, chlorzoxazone, ethoxybenzamide and sildenafil.
Comment
These data raise concerns about the safety of consumers using CHMs. These concerns relate to the regularity with which adulterations have been documented across a range of countries, to the nature of the adulterants which include powerful drugs and to the nature of some of the adverse effects associated with adulteration. One fatality [8] and at least six potentially life-threatening events [10, 11, 16, 17, 22] are on record. Phenylbutazone, phenytoin, glibenclamide and corticosteroids are some of the adulterants associated with serious adverse events. The concerns are heightened by the ready availability of CHMs through shops, therapists as well as mail order and the internet.
Many consumers are motivated to try CHMs through a misconception that these remedies are inherently safe [30], and there is evidence that the (UK) daily press is biased in favour of alternative treatments [31]. About half of individuals using CHMs do not tell their physician about it [1]. This level of noncommunication further increases the risk as doctors might fail to diagnose adverse effects caused by treatments of which they are not aware.
The relative scarcity of case reports could indicate that the problem of adulteration is, in fact, minimal. Whilst one would hope that this is true, several lines of evidence indicate that the risk is by no means negligible. The evidence summarized above is likely to be an incomplete underestimate. Underreporting of detected problems is likely to be sizeable. Moreover, those cases that are published tend to appear in the `letters' section of medical journals where they are often not retrievable through computerized literature searches. In the case of this review, many such articles could be included because the author, for more than a decade, has regularly hand-searched many journals for adverse effects associated with alternative therapies. Analytical investigations [6, 21, 25–29] of samples collected in various parts of the world perhaps provide the best indication of the size of the problem. It is, therefore, important to note that 27 and 7% of samples from Taiwan and the US, respectively, contained pharmacological agents [6, 27].
How could the risk to patients be minimized? An appropriate strategy should follow several avenues. First, the consumer should be informed that `natural' does not necessarily mean `free of risk' and that adverse effects because of CHMs are an undeniable reality. It seems obvious that the lay press has a responsibility in this [31]. Secondly, patients and physicians should be encouraged to talk about the use of CHMs and other complementary/alternative treatments [32]. Thirdly, regulators must consider effective measures to prevent adulteration of CHMs in the future.
It is concluded that adulteration of CHMs with conventional drugs is a potentially serious problem which has put consumers at risk. Means of minimizing this risk must be found and implemented.
