ReviewQuality and safety of Chinese herbal medicines guided by a systems biology perspective
Graphical abstract
The present review proposes a systems biology approach for screening extracts of Chinese herbal medicines to detect biomarkers for bioactivity in cell lines, animal models, and subsequently in human volunteers via clinical studies. The data obtained can be linked and analyzed by means of megavariate data analysis. The latter is a powerful technique that analyses data sets with a large number of variables and correlates for instance metabolomics fingerprints with a certain phenotype of bioactivity, toxicity or efficacy. Using these biomarkers or biomarker fingerprints, it is possible to offer better quality assurance and safety for herbal formulations.
Introduction
Chinese herbal medicine is often referred as Chinese materia medica (CMM). The use of CMM in the practice of Chinese medicine (CM) has a history of several thousands of years and has developed into a unique holistic health care system for the prevention, diagnosis and treatment of diseases. The human body is a complex and highly interconnected system, which is dynamically regulated within boundaries, the so-called homeostasis. The strategy of CM is based on supporting the self-healing capabilities of the body (salutogenesis) to recover from an imbalanced state. This approach is a fine-tuned at the individual level by optimizing each formula and is as such not addressing a disease with a single chemical compound or aiming at relieving a single symptom. In practice a Chinese medicine practitioner uses a unique detailed diagnostic procedure, not familiar to Western medicine, in order to prescribe a personalized mixture of CMM that the patient would typically take orally as an aqueous decoction. In the formula, each herb contains many compounds that possess concerted actions (Chan and Lee, 2002, Chan, 2005). A successful formula organizes these concerted actions derived from different herbs to create holistic, multi-target, multi-dimensional pharmacological actions to achieve personalized therapy. Such an approach is not yet embedded in Western medicine, but the advance of pharmacogenomics and systems biology have created the building blocks to bridge this CMM approach with modern pharmacology (Wang et al., 2005a, Van der Greef et al., 2006, Van der Greef and McBurney, 2005).
Currently, the practice of CMM is not only popular in China and some Asian regions; but also it is appreciated worldwide. A large-scale study of the Chinese population of Taiwan showed that from 1996 to 2001, more than 60% of all subjects have used Chinese medicine during the 6-year interval. CMMs (85.9%) were the most common modality (Chen et al., 2007). It was estimated that more than 1.5 billion people all over the world are trusting in the efficacy and safety of Chinese medicine (Hosbach et al., 2003). In the ‘Western world’, the term ‘alternative’ medicine is now often replaced by ‘complementary’ medicine. This emphasizes the complimentary nature of both developed medical systems. The latest term ‘integrative’ medicine underpin the gain that can be obtained when Western and complementary modalities are used together (Wang et al., 2005a). Parallel to this increased popularity, clinical pharmacological interest in the quality, safety and efficacy of CMM and herbal remedies in general have also grown. An aqueous decoction from a mixture of CMM can be viewed as a source of many chemical entities, and side effects are inevitable especially when not taken according to the ‘CM practitioners’ advice. Compared with the safety of pharmaceutical medicines, the investigation of toxicity of CMM is far more difficult (Chan, 2005). An estimated number of 11,145 medicines retrieved from medicinal plants are known in China (Huang et al., 2004). Their efficacy and toxicity are mostly based on historical, long term clinical experience instead of modern scientific evaluation. A challenge is the variation in chemical contents caused by the variation of growth during the day–night rhythm, seasonal change, age and polymorphisms within one species (Zhu, 1998, Chang et al., 2006). The variation in chemical contents contributes to varying observations of potential toxicity of CMMs. Furthermore, the physiological status of the body plays a role in the toxicity as it may reduce or promote toxicity by molecular interactions. Moreover, the causes of adverse reactions associated with CMM are complex and diverse (Ko, 2004). Important to note is that given the personalized character of CMM, different scientific methods need to be applied rather than the golden standard randomized, cross-over, double blinded clinical trial designs. Moreover one could argue that a practical evaluation over many more patients than normally used in clinical trials yields a better insight. Typically clinical trials for Western medicine are started with evidence for possible positive action in human, but only 10% of the new chemical entities tested pass the clinical trial research often with toxicology as major stumble block. After the introduction into the market the practice-based regime is entered and a significant number of newly introduced drugs need to be withdrawn because of serious side effects. In principle the sequence of practice-based and evidence based research is reversed in the current research. However, the lack of large scale comparisons between doctors and the variability of the herbal materials as well as the production, create a challenge for a more meta-analysis view. The limited knowledge collected today makes it difficult to diagnose the toxic effects derived from herbal medicines in general (Chan et al., 2005). On the other hand modern Chinese medicines produced under good manufacturing practice (GMP) and distributed through hospital channels provided a clear view on the efficacy and safety of a number of formulas. Traditional knowledge on the practice of processing of crude CMM and the knowledge of the optimal combination of herbs in formulas to limit or reduce toxicity are as important as the efficacy issue.
In recent years, modern chemical, physical and biological methods are applied for the investigation of the toxicity of CMM and significant progress has been achieved. Poisonous compounds from individual toxic CMMs have been identified and the mechanisms of toxicity are under scientific investigations. Despite the great progress, safety of CMM is still a difficult task, partly due to the complexity of CMM but also due to the lack of appropriate approaches within toxicity research of complex herbal mixtures. In this paper, we will give a general introduction on the safety of CMM. Furthermore, the systems toxicology approach is addressed as a promising tool to investigate CMM toxicity.
Section snippets
Historical safety evaluation of CMM
The toxicity of potent CMM was recorded in the earliest Chinese Pharmacopoeia (ShenNong BenChao Jing) in the East Han dynasty (25–220 AD) (Liu et al., 2003, Liang and Gao, 1992), a total of 365 CMMs derived from plants, animals and minerals were recorded as medicines and classified into superior, average and inferior medicines. In the inferior category 125 medicines were considered to be toxic or with side effects. Cautions on these medicines were recommended: to be used only for treatment of
CMM and constituents with known side effects in the Chinese Pharmacopoeia
All medicines when used inappropriately may turn beneficial pharmacological actions into toxicity. From the statements of Paracelsus in the fifteenth century and well-established knowledge in modern toxicology it is realized that dosage determines the toxicity of compounds. This is why Table 1 contains information about the compound dose which causes lethality or specific effects. Therefore, herbs regarded as nontoxic may have potential to cause adverse events. Ginseng, is a well-known safe
Application of systems toxicology in toxicity investigations
All medicinal products used for human intervention should have proven quality, safety and efficacy (QSE). In Western medicine several factors are taken in account that might influence the final drug response. Differences in drug metabolizing enzymes can give an increase or decrease in active or toxic constituents and differences in transporters will affect the bioavailability of drugs in cells, while different drug targets will affect the efficacy. Small molecules and proteins can also
From pharmacovigilance to mechanisms of toxicity
Herbal medicines are complex to evaluate with regards to toxicity and efficacy effects using conventional methodological approaches. This complexity includes chemical complexity, in particular in prescriptions containing multiple herbs, the lack of known synergetic active ingredients, the risk of contaminants such as pesticides, heavy metals and addition of other ingredients (sometimes pharmaceuticals), deterioration and variation in composition (Chan, 2005). Moreover interactions between CMM
Origin of the CMM from the Aconitum species
Radix Aconitum refers to the root part of the medicinal plant that belongs to the genus of the family Ranunculaceae and is comprised of about 400 species of which 166 are endemic in China (http://www.efloras.org/flora_page.aspx?flora_id=2). The most well-known species is Aconitum napellus (Monk's hood wolfsbane, aconite). Among them, only two species are used in CMM; Aconitum carmichaeli Debx and Aconitum kusnezoffi Reichb. The herbal medicines in the China Pharmacopoeia are Radix A. carmichaeli
Conclusion
In the present review, the safety of CMM and CMM products, and factors modulating their toxicity has been considered. These factors exert effects on the final reactions of the body to the herbal medicines because of the many compounds within multi-herbal preparations or in single herbal preparations. The 59 toxic herbs, which were identified and discussed shows that toxicological information about these CMM is limited. The alkaloids and terpenes were the two major classes of toxins. The
Acknowledgements
We are grateful for Dr. Suzan Wopereis for her kind help in conducting the Metacore and Metadrug analysis, Dr. Andre Schram for valuable discussion. The Sino-Dutch center for Preventive and Personalized Medicine is jointly supported by the China International Science and Technology Cooperation Program (2007DFA31060) and National Key Technologies R&D Program (2006BAI11B07) from the Ministry of Science and Technology of China, the Netherlands Genomics Initiative (NGI), the Netherlands
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