Systems approaches and polypharmacology for drug discovery from herbal medicines: An example using licorice

Ethnopharmacological relevance

Licorice, one of the oldest and most popular herbal medicines in the world, has been widely used in traditional Chinese medicine as a cough reliever, anti-inflammatory, anti-anabrosis, immunomodulatory, anti-platelet, antiviral (hepatitis) and detoxifying agent. Licorice was used as an example to show drug discovery from herbal drugs using systems approaches and polypharmacology.

Aim of the study

Herbal medicines are becoming more mainstream in clinical practice and show value in treating and preventing diseases. However, due to its extreme complexity both in chemical components and mechanisms of action, deep understanding of botanical drugs is still difficult. Thus, a comprehensive systems approach which could identify active ingredients and their targets in the crude drugs and more importantly, understand the biological basis for the pharmacological properties of herbal medicines is necessary.

Materials and methods

In this study, a novel systems pharmacology model that integrates oral bioavailability screening, drug-likeness evaluation, blood–brain barrier permeation, target identification and network analysis has been established to investigate the herbal medicines.

Results

The comprehensive systems approach effectively identified 73 bioactive components from licorice and 91 potential targets for this medicinal herb. These 91 targets are closely associated with a series of diseases of respiratory system, cardiovascular system, and gastrointestinal system, etc. These targets are further mapped to drug–target and drug–target–disease networks to elucidate the mechanism of this herbal medicine.

Conclusion

This work provides a novel in silico strategy for investigation of the botanical drugs containing a huge number of components, which has been demonstrated by the well-studied licorice case. This attempt should be helpful for understanding definite mechanisms of action for herbal medicines and discovery of new drugs from plants.     

Evidence-based toxicity evaluation and scheduling of Chinese herbal medicines

Ethnopharmacological relevance

While there is an increasing number of toxicity report cases and toxicological studies on Chinese herbal medicines, the guidelines for toxicity evaluation and scheduling of Chinese herbal medicines are lacking.

Aim

The aim of this study was to review the current literature on potentially toxic Chinese herbal medicines, and to develop a scheduling platform which will inform an evidence-based regulatory framework for these medicines in the community.

Materials and methods

The Australian and Chinese regulations were used as a starting point to compile a list of potentially toxic herbs. Systematic literature searches of botanical and pharmaceutical Latin name, English and Chinese names and suspected toxic chemicals were conducted on Medline, PubMed and Chinese CNKI databases.

Results

Seventy-four Chinese herbal medicines were identified and five of them were selected for detailed study. Preclinical and clinical data were summarised at six levels. Based on the evaluation criteria, which included risk–benefit analysis, severity of toxic effects and clinical and preclinical data, four regulatory classes were proposed: Prohibited for medicinal usage, which are those with high toxicity and can lead to injury or death, e.g., aristolochia; Restricted for medicinal usage, e.g., aconite, asarum, and ephedra; Required warning label, e.g., coltsfoot; and Over-the-counter herbs for those herbs with a safe toxicity profile.

Conclusion

Chinese herbal medicines should be scheduled based on a set of evaluation criteria, to ensure their safe use and to satisfy the need for access to the herbs. The current Chinese and Australian regulation of Chinese herbal medicines should be updated to restrict the access of some potentially toxic herbs to Chinese medicine practitioners who are qualified through registration.     

Future development of global regulations of Chinese herbal products

Ethnopharmacological relevance

GP-TCM is the first EU-funded Coordination Action consortium dedicated to traditional Chinese medicine (TCM) research. One of the key deliverables of the Work Package 7 in GP-TCM was to investigate information of the existing requirements for registration of TCM products listed by global regulatory bodies. The paper aims to collate data and draw comparison of these regulations. Case studies are also presented to illustrate the problems involved in registering TCM products in different regions worldwide.

Materials and methods

A collaborative network task force was established during the early stage of the GP-TCM project and operated through exchanges, teleconferences and focused discussions at annual meetings. The task force involved coordinators, academics who are actively involved with R&;D of Chinese herbal medicines, experts on monographic standards of Chinese materia medica, representatives from regulatory agencies, experts from industries in marketing Chinese medicines/herbal medicines and natural products. The co-ordinators took turns to chair teleconferences, led discussions on specific issues at AGM discussion sessions, at joint workshops with other work-packages such as WP1 (quality issues), WP3 (toxicology issues) and WP6 (clinical trial issues). Collectively the authors were responsible for collating discussion outcomes and updating written information.

Results

A global overview of regulations on herbal registration has been compiled during the three years of the consortium. The regulatory requirements for registration of herbal products in the EU and China were compared, and this is extended to other regions/countries: Africa, Australia, Brazil, Canada, Japan, Russia, South Korea, Taiwan, and the United States. A wide variation of the regulations for the categories of herbal products exists: food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use, food supplement); cosmetic, traditional herbal medicine products; herbal medicines for human use and veterinary use.

Conclusion

The regulatory issues for registration of herbal products are complicated among the countries and regions worldwide. The information summarised in the text is for reference only. Some regulations which are presented in this review are still in legislation process and may change in due course. Before taking any regulatory action, readers are advised to consult current official legislation and guidance and/or to seek appropriate professional advice. The lessons learnt from global regulation of TCM will provide valuable insights for regulation of other traditional medicine such as Ayurveda and Unani medicine, as well as other forms of indigenous medicine. The WHO is well placed to co-ordinate a consultation process with the aim of putting forward suggestions for harmonisation to key regulatory agencies.     

Prescription pattern of Chinese herbal products for hypertension in Taiwan: A population-based study

Ethnopharmacological relevance

Traditional Chinese medicine (TCM) has been commonly used in Asia country. The aim of this study is to analyze the utilization of TCM among hypertensive patients in Taiwan.

Materials and methods

The use of TCM for primary hypertensive patients was evaluated using a randomly sampled cohort of 1,000,0s recruited from the National Health Insurance Research Database in 5-year period from 2006 to 2010.

Results

Overall, 49.7% (n=42,586) of primary hypertension utilized TCM and 12.1% (n=5132) of them used TCM for the treatment of hypertension. Among the top 10 most frequently prescribed herbal formulae, Tian-Ma-Gou-Teng-Yin, Gout-Teng-San, Liu-Wei-Di-Huang-Wang and its derivatives were found to be the most common herbal formulae prescribed by TCM doctors for the treatment of hypertension in Taiwan.

Conclusion

This study showed the utilization pattern of Chinese herbal product in patients with hypertension. Further researches and clinical trials are needed to evaluate the efficacy of these Chinese formulae or its ingredients in treating hypertension.     

Fighting fire with fire: poisonous Chinese herbal medicine for cancer therapy

Ethnopharmacological relevance

Following the known principle of “fighting fire with fire”, poisonous Chinese herbal medicine (PCHM) has been historically used in cancer therapies by skilled Chinese practitioners for thousands of years. In fact, most of the marketed natural anti-cancer compounds (e.g., camptothecin derivatives, vinca alkaloids, etc.) are often known in traditional Chinese medicine (TCM) and recorded as poisonous herbs as well. Inspired by the encouraging precedents, significant researches into the potential of novel anticancer drugs from other PCHM-derived natural products have been ongoing for several years and PCHM is increasingly being recognized as a gathering place for promising anti-cancer drugs. The present review aimed at giving a rational understanding of the toxicity of PCHM and, especially, providing the most recent developments on PCHM-derived anti-cancer compounds.

Materials and methods

Information on the toxicity and safety control of PCHM, as well as PCHM-derived anti-cancer compounds, was gathered from the articles, books and monographs published in the past 20 years.

Results

Based on an objective introduction to the CHM toxicity, we clarified the general misconceptions about the safety of CHM and summarized the traditional experiences in dealing with the toxicity. Several PCHM-derived compounds, namely gambogic acid, triptolide, arsenic trioxide, and cantharidin, were selected as representatives, and their traditional usage and mechanism of anti-cancer actions were discussed.

Conclusions

Natural products derived from PCHM are of extreme importance in devising new drugs and providing unique ideas for the war against cancer. To fully exploit the potential of PCHM in cancer therapy, more attentions are advocated to be focused on their safety evaluation and mechanism exploration.     

Comparison of effectiveness and safety between granules and decoction of Chinese herbal medicine: a systematic review of randomized clinical trials

Background

The clinical use of Chinese herbal medicine granules is gradually increasing. However, there is still no systematic review comparing the effectiveness and safety of granules with the more traditional method of herbal decoctions.

Method

A literature search was conducted using China National Knowledge Infrastructure Databases (CNKI), Chinese Science and Technology Periodical Database (VIP), China Biomedical Database web (CBM), Wanfang Database, PubMed, and the Cochrane Library until March 10, 2011. Clinical controlled trials (CCTs) including randomized trials (RCTs) comparing the effectiveness and safety between Chinese herbal medicine granules and decoction were included. Two authors conducted the literature searches, and extracted data independently. The assessment of methodological quality of RCTs was based on the risk of bias from the Cochrane Handbook, and the main outcome data of trials were analyzed by using RevMan 5.0 software. Risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI) were used as effect measure.

Results

56 clinical trials (n = 9748) including 42 RCTs and 14 CCTs were included, and all trials were conducted in China and published in Chinese literature. 40 types of diseases and 15 syndromes of traditional Chinese medicine (TCM) were reported. Granules were provided by pharmaceutical companies in 13 trials. The included RCTs were of generally low methodological quality: 7 trials reported adequate randomization methods, and 2 of these reported allocation concealment. 10 trials used blinding, of which 5 trials used placebo which were delivered double blind (blinded participants and practitioners). 98.2% (55/56) of studies showed that there was no significant statistical difference between granules and decoctions of Chinese herbal medicine for their effectiveness. No severe adverse effects in either group were reported.

Conclusions

Due to the poor methodological quality of most of the included trials, it is not possible to reach a definitive conclusion whether both Chinese herbal medicine granules and decoctions have the same degree of effectiveness and safety in clinical practice, but this preliminary evidence supports the continued use of granules in clinical practice and research. Standardization of granules and further more rigorous pharmacological, toxicological and clinical studies are needed to demonstrate the equivalence with decoctions.     

Compatibility art of traditional Chinese medicine: From the perspective of herb pairs

Ethnopharmacological relevance

Over the past decades, research of traditional Chinese medicine (TCM) mainly focused on developing potential candidates from Chinese medicinal herbs, while the wisdom of applying these traditional herbs has not been paid as much attention as it deserves. As is well-known, multi-herb therapy is one of the most important characteristics of TCM, but the modernization drive of this conventional wisdom has faced many obstacles due to its unimaginable complexity. Herb pairs, the most fundamental and the simplest form of multi-herb formulae, are a centralized representative of Chinese herbal compatibility. In light of their simplicity and the basic characteristics of complex formulae, herb pairs are of great importance in the studies of herb compatibility.

Materials and methods

A systematic search of herb pair related research was carried out using multiple online literature databases, books and monographs published in the past 20 years.

Results

A comprehensive introduction to the compatibility of TCM, the position of herb pairs in TCM and the progresses of several famous herb pairs were provided in this review. Furthermore, the clinical study and the future research trends of herb pairs were also discussed.

Conclusions

Herb pairs have played, and may continue to play a key role in full investigation of general herb compatibility for their indispensable position in TCM. Much more research is needed for the standardization, safety evaluation, and mechanism exploration of herb pairs.     

A strategy for evaluating antipyretic efficacy of Chinese herbal medicines based on UV spectra fingerprints

Ethnopharmacological relevance

Quality analysis and control of Chinese herbal medicines (CHM) or herbal medicines (HM) are being more and more investigated based on fingerprint analysis, and there are also some researches on correlating fingerprints of CHM to their efficacy. Multi-component analysis methods together with fingerprints are considered potential useful tools to select candidate herbal drugs from extracts of herbs in pharmacological/bio-prospecting investigations.

Aim of the study

To explore a strategy for evaluating efficacy strength of CHM samples based on their spectra fingerprints and validate it.

Methodology

Radix bupleuri (RB), a typical Chinese medicinal herb for relieving exterior syndrome, and Flos lonicerae (FL), Fructus forsythiae (FF), and Radix isatidis (RI) that are widely applied Chinese herbs for heat clearing and detoxifying, were selected as herbal sources. The aqueous extracts, volatile oils and mixtures of the extracts and oils of the four herbs, plus Ibuprofen suspension (IS), Shuanghuanglian oral liquid (SHL), mixture of SHL and the volatile oils of FL and FF, were used for subject samples to do antipyretic experiments on rats. Ultraviolet spectra were used as the spectra fingerprints to represent chemical characteristics of the samples. Principal component analysis (PCA) and canonical correlation analysis (CCA) were adopted as evaluation tools to establish the correlation between pharmacological and spectra data, from which a spectral index for evaluating antipyretic effects of CHM samples was constructed. Furthermore, four compound samples were designed by mixing 50% volatile oils and 50% aqueous extracts of the four herbs with different ratios to validate the strategy.

Results

Efficacy sequence of the 15 calibrating and 4 validating CHM samples, defined by the first canonical correlative variable U₁ of their UV spectra, was consistent with that given by pharmacological experiments.

Conclusions

The strategy proposed in this study could be applied to evaluate efficacy strength of CHM and helpful for screening candidate herbal drugs from different herbs or prepared by different technologies.     

Ethnomedicinal knowledge and relative importance of indigenous medicinal plants of Cholistan desert,Punjab Province,Pakistan

Ethnopharmacological relevance

Ethnomedicinal studies are significant for the discovery of new crude drugs from indigenous reported medicinal plants. The current study aimed to report the indigenous medicinal knowledge of plants and herbal remedies used as folk medicines in Cholistan desert, Punjab Province, Pakistan.

Material and methods

Rapid appraisal approach (RAA), semi-structured interviews, group meetings with herbalists, landowners and local people having awareness about the medicinal action of plants were employed to collect the data.

Results and discussions

This study reports 70 medicinal plants belonging to 27 families that were disseminated among 60 different genera and Poaceae was the predominant family over others with 13 reported medicinal plants. Among plant parts, leaves were the dominant over others with 26.4% used in herbal preparations followed by the stem (25.2%), fruit (21.5%), flower (16.3%), seed (6.5%), bark and pod (02%). Haloxylon recurvum exhibited the highest use vale (UV) 0.83 while least UV was exhibited by Mollugo cerviana that was 0.16.

Conclusion

Important medicinal plants, reported in this study have been screened for phytochemical and pharmaceutical activities in different parts of the globe. It is recommended that reported medicinal plants having potent action for cancer and hepatitis must be screened for pharmacological activities.     

The traditional Chinese medicine prescription patterns of Sjögren׳s patients in Taiwan: A population-based study

Ethnopharmacological relevance

Traditional Chinese medicines (TCM), when given for symptom relief, have gained widespread popularity among Sjögren?s patients. The aim of this study was to analyze the utilization of TCM among Sjögren?s patients in Taiwan.

Materials and methods

The usage, frequency of service, and the Chinese herbal products prescribed among Sjögren?s patients were evaluated in a cohort of 1,000,000 beneficiaries recruited from the National Health Insurance Research Database. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of a TCM.

Results

More than 90% of Sjögren?s patients received TCM out-patient services at least once during the study period. Patients with secondary Sjögren?s syndrome were more likely to seek TCM treatment than those with primary Sjögren?s syndrome. The aOR for those suffering from at least one rheumatologic disease was 1.56 (95% CI: 1.26–1.93), those with two rheumatologic diseases was 1.98 (95% CI: 1.29–3.04), while those with three or more rheumatologic diseases was 7.86 (95% CI: 1.09–56.58). Compared to Sjögren?s patients who used no medical treatment, the aOR for those who took one type of conventional medication was 1.55 (95% CI: 1.25–1.92), those who took two types was 1.98 (95% CI: 1.60–2.47) while those who took three or more types was 2.91 (95% CI: 2.20–3.84). Qi-Ju-Di-Huang-Wan (Lycium Berry, Chrysanthemum, and Rehmannia Pill) was the most frequently prescribed formula among Sjögren?s patients.

Conclusion

Qi-Ju-Di-Huang-Wan is the most commonly prescribed Chinese herbal formula for Sjögren?s syndrome and its effects should be taken into account by healthcare providers.     

Naturally derived anti-inflammatory compounds from Chinese medicinal plants

Ethnopharmacological relevance

Though inflammatory response is beneficial to body damage repair, if it is out of control, it can produce adverse effects on the body. Although purely western anti-inflammatory drugs, orthodox medicines, can control inflammation occurrence and development, it is not enough. The clinical efficacy of anti-inflammation therapies is unsatisfactory, thus the search for new anti-inflammation continues. Chinese Material Medica (CMM) remains a promising source of new therapeutic agents. CMM and herbal formulae from Traditional Chinese Medicine (TCM), unorthodox medicines, play an improtant anti-inflammatory role in multi-targets, multi-levels, and multi-ways in treating inflammation diseases in a long history in China, based on their multi-active ingredient characteristics. Due to these reasons, recently, CMM has been commercialized as an anti-inflammation agent which has become increasingly popular in the world health drug markets. Major research contributions in ethnopharmacology have generated vast amount of data associated with CMM in anti-inflammtion aspect. Therefore, a systematic introduction of CMM anti-inflammatory research progress is of great importance and necessity.

Aim of the study

This paper strives to describe the progress of CMM in the treatment of inflammatory diseases from different aspects, and provide the essential theoretical support and scientific evidence for the further development and utilization of CMM resources as a potential anti-inflammation drug through a variety of databases.

Material and methods

Literature survey was performed via electronic search (SciFinder^®, Pubmed^®, Google Scholar and Web of Science) on papers and patents and by systematic research in ethnopharmacological literature at various university libraries.

Results

This review mainly introduced the current research on the anti-inflammatory active ingredient, anti-inflammatory effects of CMM, their mechanism, anti-inflammatory drug development of CMM, and toxicological information.

Conclusion

CMM is used clinically to treat inflammation symptoms in TCM, and its effect is mediated by multiple targets through multiple active ingredients. Although scholars around the world have made studies on the anti-inflammatory studies of CMM from different pathways and aspects and have made substantial progress, further studies are warranted to delineate the inflammation actions in more cogency models, establish the toxicological profiles and quality standards, assess the potentials of CMM in clinical applications, and make more convenient preparations easy to administrate for patients. Development of the clinically anti-inflammatory drugs are also warranted.     

Value chains of herbal medicines--research needs and key challenges in the context of ethnopharmacology

Background

Value chain analyses are commonly used to understand socioeconomic and power relationships in the production chain from the initial starting material to a final (generally high value) product. These analyses help in terms of understanding economic processes but also have been used in the context of socioeconomic and socioecological research.

Aims of the study

However, there is a gap in the ethnopharmacological literature in terms of understanding what relevance a critical analysis of value chains of herbal medicines could have. Here we provide a research framework for achieving such an analysis.

Methods

An extensive review of the literature available on value chains and their analysis was conducted, based both on a systematic online search of the relevant literature and a hand search of bibliographies and discussions with experts in value chain analysis

Results

While the concept of value chains is commonly used in the relevant industries, very few studies investigate the value chains of herbal medicines and products derived from them. The studies identified mostly look at socio-ecological aspects, especially in the context of sustainable resource use. We suggest an analytical framework which can help in understanding value chains in the context of ethnopharmacology and can serve as a basis for addressing questions related to value chains and their relevance in ethnopharmacology.

Conclusions

We identified a crucial gap in current ethnopharmacological and medicinal plant research which impacts on a wide-range of factors relevant for a sustainable, socio-culturally equitable and safe supply of herbal medicines.     

Herbal medicines for the prevention of alcoholic liver disease: A review

Ethnopharmacological relevance

Long-term excess alcohol exposure leads to alcoholic liver disease (ALD)—a global health problem without effective therapeutic approach. ALD is increasingly considered as a complex and multifaceted pathological process, involving oxidative stress, inflammation and excessive fatty acid synthesis. Over the past decade, herbal medicines have attracted much attention as potential therapeutic agents in the prevention and treatment of ALD, due to their multiple targets and less toxic side effects. Several herbs, such as Cnidium monnieri (L.) Cusson (Apiaceae), Curcuma longa L. (Zingiberaceae) and Pueraria lobata (Willd.) Ohwi (Leguminosae), etc., have been shown to be quite effective and are being widely used in China today for the treatment of ALD when used alone or in combination.

Aim of the review

To review current available knowledge on herbal medicines used to prevent or treat ALD and their underlying mechanisms.

Materials and methods

We used the pre-set searching syntax and inclusion criteria to retrieve available published literature from PUBMED and Web of Science databases, all herbal medicines and their active compounds tested on ALD induced by both acute and chronic alcohol ingestion were included.

Results

A total of 40 experimental studies involving 34 herbal medicines and (or) active compounds were retrieved and reviewed. We found that all reported extracts and individual compounds from herbal medicines/natural plants could be beneficial to ALD, which might be attributed to regulate multiple critical targets involved in the pathways of oxidation, inflammation and lipid metabolism.

Conclusions

Screening chemical candidate from herbal medicine might be a promising approach to drug discovery for the prevention or treatment of ALD. However, further studies remain to be done on the systematic assessment of herbal medicines against ALD and the underlying mechanisms, as well as their quality control studies.     

Good practice in reviewing and publishing studies on herbal medicine, with special emphasis on traditional Chinese medicine and Chinese materia medica

Ethnopharmacological relevance

Studies on traditional Chinese medicine (TCM), like those of other systems of traditional medicine (TM), are very variable in their quality, content and focus, resulting in issues around their acceptability to the global scientific community. In an attempt to address these issues, an European Union funded FP7 consortium, composed of both Chinese and European scientists and named “Good practice in traditional Chinese medicine” (GP-TCM), has devised a series of guidelines and technical notes to facilitate good practice in collecting, assessing and publishing TCM literature as well as highlighting the scope of information that should be in future publications on TMs. This paper summarises these guidelines, together with what has been learned through GP-TCM collaborations, focusing on some common problems and proposing solutions. The recommendations also provide a template for the evaluation of other types of traditional medicine such as Ayurveda, Kampo and Unani.

Materials and methods

GP-TCM provided a means by which experts in different areas relating to TCM were able to collaborate in forming a literature review good practice panel which operated through e-mail exchanges, teleconferences and focused discussions at annual meetings. The panel involved coordinators and representatives of each GP-TCM work package (WP) with the latter managing the testing and refining of such guidelines within the context of their respective WPs and providing feedback.

Results

A Good Practice Handbook for Scientific Publications on TCM was drafted during the three years of the consortium, showing the value of such networks. A “deliverable – central questions – labour division” model had been established to guide the literature evaluation studies of each WP. The model investigated various scoring systems and their ability to provide consistent and reliable semi-quantitative assessments of the literature, notably in respect of the botanical ingredients involved and the scientific quality of the work described. This resulted in the compilation of (i) a robust scoring system and (ii) a set of minimum standards for publishing in the herbal medicines field, based on an analysis of the main problems identified in published TCM literature.

Conclusion

Good quality, peer-reviewed literature is crucial in maintaining the integrity and the reputation of the herbal scientific community and promoting good research in TCM. These guidelines provide a clear starting point for this important endeavour. They also provide a platform for adaptation, as appropriate, to other systems of traditional medicine.