Quality and safety of Chinese herbal medicines guided by a systems biology perspective

Abstract

Chinese herbal medicines, often referred as Chinese materia medica (CMM), are comprised of a complex multicomponent nature. The activities are aimed at the system level via interactions with a multitude of targets in the human body. This review aims at the toxicity aspects of CMM and its preparations at the different steps of production; harvesting, processing and the final formulation. The historic perspective and today's issues of the safety of CMM are introduced briefly, followed by the descriptions of the toxic CMM in the current Chinese Pharmacopoeia (2005). Subsequently, several aspects of safety are illustrated using a typical example of a toxic CMM, Aconitum roots, and some recent findings of our own research are included to illustrate that proper processing and multi-herbs formulation can reduce the level of toxic components. This also explains that in CMM, some herbs, such as Aconitum, Ephedra species are never used as single herb for intervention and that aconite is only used when it is processed and in combination with specific matched other herbs. The formulation principle of multi-herbs intervention strategy is a systems approach for the treatment and prevention of disease. In this light, the role of systems toxicology in the safety and quality of Chinese herbal medicine is proposed as a promising method. Moreover the principles of practiced-based and evidence-based research are discussed from a symbiotic perspective.

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.