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Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition.

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Chapter 22Integration of Herbal Medicine into Evidence-Based Clinical Practice

Current Status and Issues

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22.1. INTRODUCTION

The integration of herbal and other forms of traditional medicine (TM) can be done in one of the following three ways: First, it can be incorporated as an integral part of a country’s formal health care system, with each being separately recognized as legitimate forms of health care within the same framework. Second, it can be practice integrated with modern medicine by individual health care practitioners. Third, traditional and modern practices can be integrated as two branches of medical science, with the ultimate incorporation of elements of both to form a new branch (World Health Organization 2000a). The incorporation of traditional and modern evidence-based medicine (EBM) as integral parts of a country’s formal health care system is most likely to be achieved and has been demonstrated to be practicable in many countries, particularly in Asian countries such as China, Japan, Korea, and India, among others (World Health Organization 2001). On the other hand, the incorporation of traditional medical modalities such as herbal medicine into modern or EBM by either the second or third method of health care integration is not easily achieved for a host of reasons, including scientific, cultural, educational, and legal.

For decades, the People’s Republic of China has touted a system of medical education in which its modern medicine practitioners have been required to receive some formal training in traditional Chinese medicine (TCM), so that they are aware of suitable approaches in TCM during their practice of Western medicines. However, documentation of its successful integration in clinical practice is lacking (Giordano, Garcia, and Strickland 2004). In Western countries, such as the United States, Australia, Canada, and members of the European Union, the popular use of herbal medicine in the form of complementary and alternative medicine (CAM) or phytomedicine in the last two to three decades has led to a multinational, multibillion dollar industry, professional and trade organizations, national and international practice and research conferences, establishment of specialized integrated medicine practices and clinics in pain management and adjunctive cancer therapy, incorporation of CAM courses in conventional medical colleges, introduction of CAM degree-level education programs, and establishment of research funding agencies such as the U.S. National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM; http://nccam.nih.gov/), and the Australian National Institute of Complementary Medicine (NICM; http://www.nicm.edu.au). As a result of these developments, the issue of integration of CAM medicine, including herbal preparations, into modern medicine has been the subject of ongoing international discussions in the last few years (Fong 2002; Barrett 2003; Ruggle 2005; Boyd 2007; Geffen 2007; Evans 2008; Grimaldi 2008; Shang et al. 2008; Jobst 2009; Joos, Musselmann, and Szecsenyl 2009).

However, proof of efficacy or safety for the vast majority of herbal medicine has not been fully established through an evidence-based approach. Further, other issues, such as scientific, cultural, educational, economical, and legal, need to be addressed. In this chapter, we examine the current status and major scientific issues or factors that affect the integration of herbal medicine into evidence-based medical therapy.

22.2. CURRENT STATUS AND MAJOR ISSUES OF INTEGRATION OF HERBAL MEDICINE IN EVIDENCE-BASED MEDICAL THERAPY

Herbal medicine is becoming increasingly used to enhance general health and well-being, and it is also used alone for specific health problems or with modern medicine (Bruno and Ellis 2005; Kennedy 2005). A recent population study on 2526 adults from the Australian state of Victoria indicated that almost a quarter of the adult population used some form of herbal medicine in 2006–2007 (Zhang et al. 2008). Similarly, about one in five or an estimated 38.2 million adults in the United States used herbs and supplements in 2002, according to the National Health Interview Survey, which interviewed 31,044 representatives of the civilian noninstitutionalized population of the United States (Kennedy 2005). Established in 1999, the Consortium of Academic Health Centers for Integrative Medicine represents 44 academic health centers in the United States and Canada. The Consortium has been working on the inclusion of CAM knowledge, such as herbal therapies, into medical school curricula and the establishment of standards for research in integrative medicine and strategies in integrating alternative treatments into clinical care.

Currently, thousands of TM and other CAM herbal products are available as therapeutic agents worldwide. Yet few of these products have been subjected to randomized clinical trials (RCTs) under the International Conference on Harmonization (ICH) Good Clinical Practice Guidelines to determine their efficacy and/or safety (International Conference on Harmonization 2010.). Of the nearly 2000 herbal medicine clinical studies listed on the Cochrane Controlled Trials Register as of June 2009, most concern single-plant herbal or phytomedicine (www.thecochranelibrary.com). In recent years, in the case of multicomponent herbal medicines, an increased number of RCTs on traditional herbal medicine has been reported in the literature (World Health Organization 2004). For example, an Australian study on a Chinese herbal medicine prescription for the treatment of allergic rhinitis concluded that level II evidence is available that may substantiate the use of Chinese herbal medicine for both seasonal and perennial allergic rhinitis (Xue et al. 2003). Unfortunately, the quality of the majority of the clinical studies of herbal medicines reported to date is of great concern due to a number of factors that have rendered the data of dubious value. In a review of 206 RCTs on herbal medicine, which was published in Medline from 1966 to 2003, important methodological components of RCTs, particularly allocation concealment, generation of the allocation sequences, and intention-to-treat analyses, were incompletely reported. In these studies, only slightly over a quarter of the trials adequately reported blinding, and one-fifth reported generation of random allocation sequences (Gagnier et al. 2006). Furthermore, an earlier review of 2938 RCTs on TCM reported in 1980–1997 (Tang, Zhan, and Ernst 1999) concluded that the majority of these studies suffered from methodological defects. For example, only 15% of these studies used blinding, the sample size was mostly less than 300 patients, the controls were inadequate, few studies used quantitative outcome measures, and the studies were short term.

There have been many nonclinical in vitro and in vivo studies on herbal medicines that have commonly supported the traditional therapeutic claims. However, systematic reviews of the study protocols or the data interpretation and validation are lacking. Further, the translation of an in vitro and/or in vivo biological/pharmacological effect of a herbal medicine to human therapeutic use may not be successful due to species differences or other mitigating circumstances, including the simple attribute of a biological or clinical outcome by the name of the mother herb, while neglecting the type of plant extract, methods of processing, and pharmaceutical formulation, which invariably contain varying content and proportions of active chemical components (Brinker 2009).

In addition to the preclinical biological or pharmacological issues, the quality of the herbal products can affect the clinical outcomes and thus can impact their successful integration into EBM. Herbal medicine quality can be substantially different due to intrinsic and extrinsic factors. Species differences, organ specificity, and diurnal and seasonal variations are examples of intrinsic factors that can affect the qualitative and quantitative accumulation of the biologically or pharmacologically active chemical constituents produced and/or accumulated in the herb. Extrinsic factors affecting the quality of the herbal medicine include environmental conditions, cultivation and field collection practices, postharvest handling, storage, manufacturing, inadvertent contamination, substitution, and intentional adulteration (Awang 1997; Huang, Wen, and Hsiao 1997; Slifman et al. 1998; Mahady, Fong, and Farnsworth 2001; Cordell 2002; Fong 2002; Chadwick and Fong 2006).

22.3. FACTORS RELEVANT TO/AFFECTING INTEGRATION OF HERBAL MEDICINE INTO MODERN MEDICAL PRACTICES

A range of interrelated quality, safety and efficacy issues could contribute to the rational and successful integration of herbal medicine into modern medical practices.

22.3.1. Herb Quality Issues

Fundamental to assuring the efficacy and reproducibility of any medicinal agent, be it a single chemical or a complex herbal mixture, is the assured quality of the product. In the case of single chemical drugs, the quality and properties are well defined and documented in pharmacopoeias or on file with regulatory agencies or marketing authorities. On the other hand, herbal medicines, be they single herbs or polyherbal products, suffer from a lack of uniformity in their chemical and physical qualities due to various factors as mentioned above. All these factors have contributed to extensive lists of herbal medicines being reported in the scientific and lay media to be of inferior and questionable quality and authenticity.

In our early postmarket surveillance of selected commercial ginseng products prepared from Panax ginseng C.A. Meyer., P. quinquefolius L., and Eleutherococcus senticosus Max (eleuthero) marketed in North America in 1995–1998, we found that 26% of these products did not meet label claims with respect to the claimed ginsenoside content of the Panax ginseng and Panax quinquefolius products (Fitzloff, Yat, and Lu 1998). Studies on the quality of St. John’s wort products showed the hypericin content ranging from 22% to 165% and silymarin content in milk thistle (Silybum marianum L. Gaertn.) products ranging from 58% to 116% of the labeled claims (Schulz, Hubner, and Ploch 1997). Gilroy et al. (2003) reported their investigation of herbal medicines sold as “echinacea” in the United States. A total of 59 products were studied (Gilroy et al. 2003) and of these, seven of nine so-called standardized products contained substantially less of the marker compounds echinacoside or cichoric acid than the stated content, with the other two being totally devoid of either compound.

Another major extrinsic quality problem concerns substitution and/or adulteration. Herbal medicines collected in the wild as well as some cultivated source materials, where more than a single species is grown in a given farm or site, can lead to nontargeted species being harvested by either accidental substitution or intentional adulteration. Substitution of Periploca sepium Bunge for Eleutherococcus senticosus (eleuthero) had been well documented (Awang 1997), and the U.S. Food and Drug Administration (FDA) had traced the original adverse reactions attributed to plantain (Plantago ovata Forsk.) as having actually been caused by Digitalis lanata Ehr., a contaminant introduced during harvesting of plantains (Slifman et al. 1998).

Unintentional in-process adulteration with heavy metals, microbial and chemical agents (pesticides, herbicides, and heavy metals), as well as with foreign matter such as insects, animals, animal parts, and animal excreta during any of the stages of source plant material production or procurement can result in unsafe source materials (Fong 2002). Besides unintentional in-process adulteration with heavy metals, it is well established that Ayurvedic medicine and TCM sometimes employ complex mixtures of plant, animal, and minerals such as lead, mercury, cadmium, arsenic, and gold in certain formulations (Ernst and Thompson Coon 2001).

Perhaps the most egregious impediment to the integration of herbal medicine into conventional medicine is the intentional adulteration of herbal medicine products with synthetic pharmaceutical drugs. Multicomponent Chinese or Ayurvedic herbal medicines have long been documented to be adulterated with synthetic anti-inflammatory drugs such as phenylbutazone, indomethacin, and/or corticoid steroids in arthritis remedies (Farnsworth 1993). A Taiwanese study on the chemical adulteration of TM found that about 24% of 2609 herbal remedy samples collected by eight major hospitals were found to contain one or more synthetic therapeutic agents (Huang, Wen, and Hsiao 1997). In more recent years, the most infamous among the documented cases was PC-SPES, a purported Chinese herbal mixture sold in the United States for the promotion of prostate health, and which was used by many prostate cancer patients for its remarkable efficacy. Unfortunately, reports proved the product to have been adulterated with estrogen, warfarin, and other pharmaceuticals (Blumenthal 2002; Cordell 2002). These cited examples are only a few of the quality control (QC) or lack of quality control issues associated with herbal medicines that greatly affect their successful integration into modern EBM.

22.3.2. Quality Assurance/Quality Control in Processing and Manufacturing/Preparation of Herbal Medicines (Good Manufacturing Practices Issues)

The most important extrinsic factor affecting the quality of herbal medicines is the lack of effective policies on quality assurance (QA)/QC in the processing and manufacturing of herbal products under good manufacturing practices (GMP; World Health Organization 2007b). These can vary from country to country (World Health Organization 1998). In some countries, herbal medicines are regulated as medicine and subject to mandated standards, whereas in others very few botanical products are available as prescription or over-the-counter (OTC) drugs.

The majority of herbal medicines marketed in the United States are sold as dietary supplements under the provisions of the Dietary Supplement Health and Education Act (DSHEA) of 1994, and have only recently been mandated by law to be produced under cGMP (Food and Drug Administration 2007). Unfortunately, the QA/QC requirements are far short of those required in the production of prescription and OTC drugs. For dietary supplements, including herbal medicines, the requirements apply only to the manufacturers of the final product and not to the dietary ingredient suppliers, which have been the source of some of the most high-profile problems of adulterated, substituted, or contaminated ingredients associated with herbal dietary supplements. A study by (Liva 2009), which serves to illustrate this problem, described some cases of poor quality controlled, unfinished herbal materials, including a hops (Hamulus lupulus) extract, that did not meet the expected chemical profile but instead appeared to contain burned maltodextrin, Asian red ginseng (Panax ginseng), and wild yam (Dioscorea villosa) extracts containing quintozene, a fungicide that is illegal to use in herbal medicine, and in a solvent residue test, a purported ethanol–water extract of milk thistle (Silybum marianum) was found to contain benzene, and a subsequent GC/ MS analysis showed 30 different acyclic and cyclic hydrocarbons, including benzene and toluene, which are known carcinogens. Until cGMP requirements are mandated and adhered to in the supply as well as in the manufacturing sides to ensure the availability of quality herbal products, herbal integration into modern medical practice will continue to pose problems.

In several countries, herbal medicines are totally unregulated. Consequently, product quality may differ from country to country, within the same country from product brand to product brand, and even from batch to batch within the same brand.

22.3.3. Herbal Mechanisms of Action, Bioavailability, and Herbs′ Chemical Constituents

The underlying mechanisms of action of herbal medicine, whether single herbal or multiple herbal formulations, have generally not been elucidated due to the lack of knowledge of identifying their contained active and/or adjuvant phytochemical constituents. The same problem applies to the study of pharmacokinetics and bioavailability. In the case of single-molecular pharmaceuticals, there is no uncertainty as to which chemical compound is to be used for pharmacokinetic and bioavailability studies. Herbal medicines are constrained by their unknown and/or unidentifiable active chemical constituents (Fong et al. 2006). Nevertheless, some investigators have attempted to conduct such studies. For example, the mechanism of action of a Chinese herbal medicine formula (consisting of seven herbs formulated based on the results of a series of in vitro experiments and a comprehensive literature review) was postulated from a study of its in vitro effect on rat peritoneal mast cells and macrophage cells (Lenon et al. 2009). It was found that the formula significantly inhibited the release of several inflammatory mediators, including histamine and prostaglandins, which led the researchers to conclude that it has multiple mechanisms and that potential synergistic effects of the individual herbal constituents could all have contributed to the actions of the formula. Unfortunately, the potential clinical antiallergic effects of the formula are yet to be tested through adequately powered RCTs, which brings into question the validity of such postulations.

22.3.4. Herb–Drug Interactions

Reports on herb–drug interactions are mainly from case reports that were inadequately documented and/or on the basis of in vitro studies (Awang and Fugh-Berman 2002). A recent review based on extensive literature search suggested that, when herbs are often administered in combination with drugs, there were only limited clinical observations on the interactions among humans (Hu et al. 2005). Nevertheless, the potential of interactions of herbal medicine with prescribed drugs or OTC drugs has been a major safety concern for clinicians as such interactions are difficult to predict and the general lack of available information on the herbs’ composition and pharmacological actions (Zhou et al. 2007).

In recent years, researchers have attempted to identify interactions between commonly used herbs and drugs. Many of them are now well known, such as the interaction between St. John’s wort and warfarin (Yue, Bergquist, and Gerden 2000; Henderson et al. 2002) or digoxin (Johne et al. 1999). A recent review concluded that 34 commonly used drugs that interacted with herbal medicines in humans had been identified. These include anticoagulants (e.g., warfarin, aspirin), antidepressants (e.g., midazolam), cardiovascular drugs (e.g., digoxin), and anticancer drugs (e.g., irinotecan; Zhou et al. 2007). If the definition of the herbal medicine extended to botanicals including fungi, algae, and other component matters, nearly 80 herbal medicines would be identified that had clinically significant interactions with drugs. Garlic, ginger, and ginkgo are among the herbs most commonly involved in herb–drug interactions (Ulbricht et al. 2008).

22.3.5. Herb-Herb Interactions

Herb–herb interactions, sometimes referred to as contraindications in the application of herbs or prescription incompatibility, were documented in ancient textbooks on TCM medicinal formulae (i.e., a mixture of herbs). TCM practitioners prescribe herbal formulae based on disease manifestation and characteristics of the herbs. The most well-documented herb–herb interactions were eighteen-incompatible-herbs and nineteen-counteracting-herbs. For example, Wu Tou (Aconitum rhizome) cannot be used with Ban Xia (Pinellia ternata rhizome; Weng, Nie, and Huang 2004), and Fu Zi (Radix Aconiti) is incompatible with Bei Mu (Bulbus Fritillariae; Xiao et al. 2005). It should be noted that evidence of the adverse reactions and/or toxicity of the combined use of these herbs was mainly derived from clinical observations in ancient times. Some experienced TCM practitioners may choose to use some combinations for various conditions (Zhang and Li 2009). Researchers have attempted to generate more scientific evidence through modern pharmacological studies, but conclusive recommendations have not yet been possible (Tang et al. 2009).

22.3.6. Efficacy Measurements: Objective Quantirable versus Subjective Quality of Life

The integration of herbal medicine into evidence-based clinical practice and research also rests on the acceptance of its scientific evidence by the conventional medical profession, including medical practitioners, pharmacists, nurses, and other health care workers. The evidence needs to be verified legitimately and scientifically according to the conventional EBM framework. Studies in other CAM modalities such as acupuncture have been designed with specific details of the experiment (e.g., kind of needle used, location of the points, depth of needle insertion, and techniques for rotating the needles) and the nature of the control method after considering a placebo effect (Sherman et al. 2002). If possible, evidence generated for herbal medicine should be derived from the most powerful method of testing the effect of treatment intervention, the RCT. With a plausible biological basis, herbal products can be evaluated through double-blinded, placebo-controlled, multicenter trials. Reflecting this, the World Health Organization (WHO) has published a number of guidelines for clinical evaluation of the herbal and TMs (World Health Organization 1993, 2000b).

The methodological robustness of outcome measures in 44 CAM trials in oncology had been recently evaluated, and it was concluded that only 37% stated an a priori hypothesis and only 20% addressed the clinical significance of the outcomes (Efficace et al. 2006). Trials with poor outcome measurements can exaggerate the estimates of treatment effects (Schulz et al. 1995). Thus, within the EBM paradigm, RCTs are suggested to be reported in accordance with the 22-item Consolidated Standards of Reporting Trials (CONSORT) checklist (available at www.consort-statement.org), such as a detailed description on patient eligibility criteria, sample size calculation, specific objectives and hypotheses, implementation of the trial, and statistical methods, regardless of whether the intervention is conventional or herbal (Gagnier et al. 2006a, 2006b).

In parallel with other methodologies necessary to the design of the trials, outcome measurement is central to the development of EBM practice of CAM, including herbal medicine (Long 2002). Thus, item 6 (outcomes) of the CONSORT checklist was recommended to reflect the intervention and indications tested while considering their underlying theories and concepts when reporting RCTs on herbal medicine intervention (Gagnier et al. 2006b). At the request of the NIH, the Institute of Medicine convened a working committee in 2005 and produced a report entitled Complementary and Alternative Medicine in the United States. In this report, the core recommendation was that “the same principles and standards of evidence of treatment effectiveness apply to all treatments, whether currently labeled as conventional medicine or CAM” (Institute of Medicine 2005, 2). From this view, for herbal medicine, like any other CAM and pharmaceutical drugs, efficacy measurements used in RCT need to be chosen in accordance with conventional scientific principles (objective and quantifiable) before their results can be generalized and can be made acceptable to the public. Perhaps one obstacle is the holistic concept and approach being emphasized by the unique philosophy of herbal medicine. For this reason, some subjective measurements, including the percentage of patients perceiving benefits and the number of patients “recovering” from the condition, were commonly reported in TCM trials (Ernst 2006). In recent years, the development of the quality of life instrument for herbal medicine research by using an EBM approach has received much attention (Leung et al. 2005; Wu et al. 2009).

22.3.7. Other Safety Issues

Other safety issues influencing herbal medicine integration into modern medicine include cultural and behavioral contexts as well as efficient communication on its use among patients, conventional medical practitioners, and herbal medicine practitioners. Over a few decades of development and with more scientific research data being published, although not all convincing, at least some promising evidence has met the EBM standard. As a result, negative attitudes and doubtful perceptions of herbal medicine may now only be held by a minority of the conventional medical profession. Nevertheless, it is of critical concern to clinicians that many herbal medicine users take herbal remedies and conventional therapies concurrently without informing their medical doctors. Such communication gaps can lead to herb–drug interactions that may be otherwise avoided.

The above-mentioned population study on 2526 Australian adults also indicated that approximately half of herbal medicine users took two forms of therapy on the same day (Zhang et al. 2008). However, only about half of these users had voluntarily informed their medical practitioners about their herbal medicine use. This finding was not striking and, in fact, the situation is similar in the United States, with only one-third of the users having informed their medical providers about their use of herbs or supplements (Kennedy, Wang, and Wu 2008). This study also found that nondisclosure of herb and supplement use was particularly common among racial and ethnic minority groups (Kennedy, Wang, and Wu 2008). Therefore, understanding the reasons for nondisclosure not only can help doctors to provide better clinical care but also to promote safe integration of herbal medicine into evidence-based medical therapy.

22.4. RESEARCH NEEDS

For effective integration of herbal medicine into modern therapeutic practices, the level of research on the preclinical and clinical efficacy of these products and their complementation of or interaction with modern pharmaceuticals must be elevated to much higher levels than is presently the case. Preliminary to these studies, clinical products must be produced by GMP from source materials acquired through good agriculture and collection practices (GACP), be botanically validated, be chemically and/or biologically standardized, and their stability be established. As mentioned previously in Section 22.3.2., few products have been so documented. Hence, the research on herbal medicines for the integrated medical use must begin with the acquisition and QC of source materials and processed starting materials. The three most important major areas of research can be defined as (1) herbal medicine quality and standardization, (2) preclinical pharmacological assessments and action mechanisms, and (3) clinical efficacy and safety assessments. Of relevance to conducting these needed studies, the WHO has published a guideline for methodologies on the research and evaluation of TM (World Health Organization 2000b) and the NIH NCCAM has published a policy on biologically active agents used in CAM and placebo materials (available at http://nccam.nih.gov/research/policies/bioactive.htm#), with which its grantees must comply for funding in support of their research projects on the herbal medicine.

22.4.1. Herbal Medicine Quality and Standardization: Quality Assurance and Quality Control

QA of herbal medicine for integrative medical use is a “ground-to-table” process spanning from the acquisition of the source material to the production of the clinical formulation. Therefore, QA/ QC research on source materials should begin from the point at which a specific plant part to be used as the “herb” is acquired by cultivation or field collection through GACP. Good agricultural practice guidelines have been established by a number of countries, and the WHO has also published a guideline on GACP (World Health Organization 2003) to assist member states in the production of quality herbs. Further, the WHO has published an example GACP for Artemisia annua L. (World Health Organization 2006). A most essential part of botanical QA is that plant materials should be identified by their scientific names (Latin binomial) rather than by common names and should be authenticated botanically according to pharmacopoeial standards employing macroscopic/organoleptic and microscopic methods. Each herb should be subjected to purity as well as contaminant tests for the presence of foreign matters, toxic metals, pesticide residues, mycotoxins, and microorganisms.

Qualitative HPLC-UV or LC-MS analysis leading to the generation of a characteristic profile (fingerprint) and the quantitation of reference marker compound concentrations, including relevant biologically active molecules of an extract of the herb, should be conducted as part of a product standardization study. Chemical standardization studies of the clinical formulation or product can be performed by quantitative HPLC-UV or LC-MS analysis, and stability studies of the final herbal preparation manufactured under GMP conditions (World Health Organization 2007b) can be monitored from the day of production by accelerated and/or real-time analysis. In the process, QC procedures must be implemented from source material acquisition to final product manufacture in order to assure the quality of the product being considered for integration into evidence-based modern medicine.

22.4.2. Preclinical Pharmacological Assessments and Action Mechanisms

Many herbs, such as Panax ginseng, possess a wide range of pharmacological activities (Scaglione, Pannacci, and Petrini 2005). Thus, it has been recommended that quality-certified standardization be a prerequisite for future laboratory and clinical investigations (Harkey et al. 2001). As in the case of single-molecule pharmaceutical drugs, herbal medications being considered for integrative therapy must first undergo preclinical pharmacological assessment for safety and efficacy, if possible. However, the biological response to a drug product may not be species transferable, and an active substance in animals may be entirely inactive in humans. On the other hand, acute and/or chronic toxicity manifestations in animal models are reliable indicators of drug safety. In current practice, acute and chronic toxicities are usually determined by experimental studies using animal models. Suitable methods for testing toxicity need to be established so that herbal ingredients and their derived products can be reliably assessed. For herbal medicines, testing for the presence of heavy metals such as lead, mercury, and arsenic should be mandatory, as these toxic substances are environmental contaminants often found accumulated in many herbs. Therefore, preclinical, pharmacological, and safety assessments represent a critical step in the scientific integration of herbal medicines into the evidence-based health care paradigm.

In addition, where feasible, the mechanisms of action or bioavailability of herbal medicines should be determined. However, as noted by Brinker (2009), single-dose pharmacokinetic or pharmacodynamic may not yield true data, especially in the cases of herbal preparations exhibiting weak pharmacological effects. As an example, CYP isozyme induction typically requires over a week of repeated dosing to manifest (Brinker 2009). Given the long history of the use of herbal medicine and increasing clinical evidence on its efficacy, extensive investigations of the chemical composition of constituent herbs and of the biological activity of the identified compounds are clearly warranted. In addition to identifying the active compounds and providing information about their mechanisms of action, it seems inevitable that such studies will lead to new and improved therapeutic agents for the treatment of human diseases. In recent years, reviews of the key chemical compounds present in the individual herbs used in the herbal formulae are most useful (Xue et al. 2004; Li and Brown 2009).

22.4.3. Clinical Efficacy and Safety Assessments

Fundamentally, conducting and reporting clinical studies on the efficacy and safety of herbal medicine should follow the context-specific elaborations of the CONSORT statement (Gagnier et al. 2006a,b). In addition to the documentation of all general aspects of RCTs (e.g., randomization, blinding, and analysis) that are known to influence the estimation of treatment effects, specific considerations are needed to attend to the unique obstacles of implementing herbal medicine trials. For many traditional herbal medicine products, the inherent complexities in their organoleptic properties, such as their taste, odor, or appearance, can be distinguished between the clinical preparations and their respective placebos, and thus are more vulnerable as comparison factors for testing their true therapeutic effects. Details of controlling this possible bias must be fully described so that the study can be replicated by other investigators. Backing by pharmacokinetics studies and reporting on adverse events and herb–drug interactions are central to the safety assessment of herbal medicine. On the other hand, systematic review and meta-analysis of the existing clinical evidence should be conducted in line with the intrinsic factors of herbal medicines. Such factors include, but are not limited to, variation in processing, sources (e.g., soil and climate), content, doses, and storage, as well as the diversity of effective ingredients of the herbal medicines.

22.5. CONCLUSIONS

It was said during the WHO Congress on TM in 2008 in Beijing, China, that “the two systems of traditional and Western medicine need not clash” (World Health Organization 2008). During the Congress, WHO member states and other stakeholders were called upon to take steps to integrate TM into national health systems. But integration of herbal medicine into modern clinical practice must be based on an EBM approach. Prior to the clinical evaluation of herbal medicine, be it a single compound, a mixture of herbal ingredients, or a complex herbal formula based on historic evidence of use, the QA/QC in source material acquisition and processing and manufacturing of the products under GMP must be addressed to assure efficacy and reproducibility. In addition to the use of scientifically irrefutable efficacy measurements, clinical studies should monitor and report adverse events, including potential drug–herb interactions. When the safety and efficacy are established in accordance with conventional scientific principles, the integration of herbal medicine into evidence-based clinical practice will likely occur.

ACKNOWLEDGMENTS

The authors wish to thank the WHO Collaborating Centre for Traditional Medicine at the School of Health Sciences, RMIT University, Bundoora, Victoria, Australia, and the WHO Collaborating Centre for Traditional Medicine at the College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, for their consent and encouragement to undertake the present collaboration.

REFERENCE

  1. Awang D. V. Quality control and good manufacturing practices: Safety and efficacy of commercial herbs. Food Drug Law J. 1997;52:341–4. [PubMed: 10343036]
  2. Awang D. V, Fugh-Berman A. Herbal interactions with cardiovascular drugs. J Cardiovasc Nurs. 2002;16(4):64–70. [PubMed: 12597263]
  3. Barrett B. Alternative, complementary, and conventional medicine: Is integration upon us? J Altern Complement Med. 2003;9(3):417–27. [PubMed: 12816630]
  4. Blumenthal M. Guest editorial: The rise and fall of PC-SPES: New generation of herbal supplement, adulterated product, or new drug? Integr Cancer Ther. 2002;1(3):266–70. [PubMed: 14667284]
  5. Boyd D. B. Integrative oncology: The last ten years-a personal retrospective. Altern Ther Health Med. 2007;13(1):56–64. [PubMed: 17283742]
  6. Brinker F. Managing and interpreting the complexities of botanical research. Herbal Gram. 2009;82:42–9.
  7. Bruno J. J, Ellis J. J. Herbal use among U.S. elderly: 2002 National Health Interview Survey. Ann Pharmacother. 2005;39(4):643–8. [PubMed: 15741417]
  8. Chadwick L, Fong H. H. S. Herb quality assurance and standardization in herb-drug interaction evaluation and documentation. In: Lam Y. W. F, Huang S. M, Hall S. D, editors. Herbal Supplement-Drug Interactions. New York: Taylor & Francis; 2006. pp. 191–203.
  9. Cochrane Collaboration. 2009. www​.thecochranelibrary.com The Cochrane Library. (accessed June 30, 2009).
  10. Cordell G. A. PCSPES: A brief overview. Integr Cancer Ther. 2002;1(3):271–86. [PubMed: 14667285]
  11. Efficace F, Horneber M, Lejeune S, Van Dam F, Leering S, Rottmann M, Aaronson N. K. Methodological quality of patient-reported outcome research was low in complementary and alternative medicine in oncology. J Clin Epidemiol. 2006;59(12):1257–65. [PubMed: 17098568]
  12. Ernst E. Methodological aspects of traditional Chinese medicine (TCM). Ann Acad Med Singapore. 2006;35(11):773–4. [PubMed: 17160191]
  13. Ernst E, Thompson Coon J. Heavy m in traditional Chinese medicines: A systematic review. Clin Pharmacol Ther. 2001;70(6):497–504. [PubMed: 11753265]
  14. Evans S. Changing the knowledge base in Western herbal medicine. Soc Sci Med. 2008;67:2098–106. [PubMed: 18952343]
  15. Farnsworth N. R. Relative safety of herbal medicines. Herbal Gram. 1993;29:36A–367H.
  16. Fitzloff J, Yat P, Lu Z. Z. Perspectives on the quality assurance of ginseng products in North America. Seoul, Korea.: Advances in Ginseng Research - Proceedings of the 7th International Symposium on Ginseng. 1998
  17. Fong H. H. S. Integration of herbal medicine into modern medical practices: Issues and prospects. Integr Cancer Ther. 2002;1(3):287–93. [PubMed: 14667286]
  18. Fong H. H. S, Pauli G. F, Bolton J. L, van Breemen R. N, Banuvar S, Shulman L, Geller S. E, Farnsworth N. R. Evidence-based herbal medicine: challenges in efficacy and safety assessments. In: Leung P. C, Fong H. H. S, Xue C. C, editors. Annals of Traditional Chinese Medicine Vol 2: Current Review of Chinese Medicine. Singapore: World Scientific; 2006. pp. 11–26.
  19. Food and Drug Administration. 2007. http://www​.fda.gov/Food​/DietarySupplements​/GuidanceComplianceRegulatoryInformation​/RegulationsLaws/ucm110858.htm Dietary supplement current good manufacturing practices (CGMPs) and interim final rule (IFR) facts. Accessed August 2, 2009.
  20. Gagnier J. J, Boon H, Rochon P, Moher D, Barnes J, Bombardier C. Recommendations for reporting randomized controlled trials of herbal interventions: Explanation and elaboration. J Clin Epidemiol. 2006a;59(11):1134–49. [PubMed: 17027423]
  21. Gagnier J. J, Boon H, Rochon P, Moher D, Barnes J, Bombardier C. Reporting randomized, controlled trials of herbal interventions: An elaborated CONSORT statement. Ann Intern Med. 2006b;144(5):364–7. [PubMed: 16520478]
  22. Gagnier J. J, DeMelo J, Boon H, Rochon P, Bombardier C. Quality of reporting of randomized controlled trials of herbal medicine interventions. Am J Med. 2006;119(9):800.e1–11.. [PubMed: 16945616]
  23. Geffen J. R. From integrative to multidimensional medicine. Altern Ther Health Med. 2007;13(1):14–8. [PubMed: 17283737]
  24. Gilroy C. M, Steiner J. F, Byers T, Shapiro H, Georgian W. Echinacea and truth in labeling. Arch Intern Med. 2003;163(6):699–704. [PubMed: 12639203]
  25. Giordano J, Garcia M. K, Strickland G. Integrating Chinese traditional medicine into a U.S. public health paradigm. J Altern Complement Med. 2004;10(4):706–10. [PubMed: 15353031]
  26. Grimaldi D. Integration of complementary and alternative medicine into mainstream health care. J Psychoso Nurs Ment Health Serv. 2008;46(10):8–9. [PubMed: 18935930]
  27. Harkey M. R, Henderson G. L, Gershwin M. E, Stern J. S, Hackman R. M. Variability in commercial ginseng products: An analysis of 25 preparations. Am J Clin Nutr. 2001;73(6):1101–6. [PubMed: 11382666]
  28. Henderson L, Yue Q. Y, Bergquist C, Gerden B, Arlett P. St. John's wort (Hypericum perforatum)?. Drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54(4):349–56. [PMC free article: PMC1874438] [PubMed: 12392581]
  29. Hu Z, Yang X, Ho P. C, Chan S. Y, Heng P. W, Chan E, Duan W, Koh H. L, Zhou S. Herb-drug interactions. A literature review. Drugs. 2005;65(9):1239–82. [PubMed: 15916450]
  30. Huang W. F, Wen K. C, Hsiao M. L. Adulteration by synthetic therapeutic substances of traditional Chinese medicine in Taiwan. J Clin Pharmacol. 1997;37:344–50. [PubMed: 9115061]
  31. Institute of Medicine. Complementary and Alternative Medicine in the United States. Washington, DC.: The National Academies Press; 2005.
  32. International Conference on Harmonization. 2010. http​.//www.ich.org/cache​/compo/276-254-1.html ICH guidelines. (accessed November 26, 2010)
  33. Jobst K. A. Editorial. Becoming and growing-what does integration mean? J Altern Complement Med. 2009;15(4):iii–iv. [PubMed: 19388853]
  34. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with anherbal extract from St. John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66(4):338–45. [PubMed: 10546917]
  35. Joos S, Musselmann B, Szecsenyl J. Integration of complementary and alternative medicine into family practice in Germany. Results of a national survey. eCAM. 2009:1–8. Epub, March 17, 2009. [PMC free article: PMC3140199] [PubMed: 19293252]
  36. Kennedy J. Herb and supplement use in the U.S. adult population. Clin Ther. 2005;27(11):1847–58. [PubMed: 16368456]
  37. Kennedy J, Wang C. C, Wu C. H. Patient disclosure about herb and supplement use among adults in the U.S. eCAM. 2008;5(4):451–6. [PMC free article: PMC2586312] [PubMed: 18955213]
  38. Lenon G. B, Xue C. C, Story D. F, Thien F, Li D. G. Inhibition of release of inflammatory mediators in rat peritoneal mast cells and murine macrophages by a Chinese herbal medicine formula (RCM-102). PhytotherRes. 2009;23(9):1270–5. [PubMed: 19173280]
  39. Leung K. F, Liu F. B, Zhao L, Fang J. Q, Chan K, Lin L. Z. Development and validation of the Chinese quality of life instrument. Health Qual Life Outcomes. 2005;3:26. [PMC free article: PMC1090607] [PubMed: 15833138]
  40. Li X. M, Brown L. Efficacy and mechanisms of action of traditional Chinese medicines for treating asthma and allergy. J Allergy Clin Immunol. 2009;123(2):297–306. quiz 307-8. [PMC free article: PMC2748395] [PubMed: 19203653]
  41. Liva R. Controlled testing. The cornerstone of all quality natural products. Integr Med. 2009;8(2):40–2.
  42. Long A. F. Outcome measurement in complementary and alternative medicine. Unpicking the effects. J Altern Complement Med. 2002;8(6):777–86. [PubMed: 12614531]
  43. Mahady G. B, Fong H. H. S, Farnsworth N. R. Lisse, The Netherlands: Swets & Zeitlinger Publishers; Botanical Dietary Supplements: Quality, Safety and Efficacy. 2001
  44. Ruggle M. Mainstreaming complementary therapies. New directions in health care. Health Affairs. 2005;24:980–90. [PubMed: 16136636]
  45. Scaglione F, Pannacci M, Petrini O. The standardised G115 Panax ginseng C. A. Meyer extract. A review of its properties and usage. Evid-Based Integr Med. 2005;2(4):195–206.
  46. Schulz K. F, Chalmers I, Hayes R. J, Altman D. G. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408–12. [PubMed: 7823387]
  47. Schulz V, Hubner W. D, Ploch M. Clinical trials with phytopharmacological agents. Phytomedicine. 1997;4:379–87. [PubMed: 23195591]
  48. Shang H, Zhang J, Clarke M, Zhang B, Li Y. Evidence-based medicine in traditional Chinese medicine. Collision and combination. J Altern Complement Med. 2008;14:893–4. [PubMed: 18928391]
  49. Sherman K. J, Hogeboom C. J, Cherkin D. C, Deyo R. A. Description and validation of a noninvasive placebo acupuncture procedure. J Altern Complement Med. 2002;8(1):11–9. [PubMed: 11890429]
  50. Slifman N. R, Obermeyer W. R, Aloi B. K, Musser S. M, Correll W. A Jr., Cichowicz S. M, Betz J. M, Love L. A. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med. 1998;339(12):806–11. [PubMed: 9738088]
  51. Tang Y. P, Wu Q. C, Ding A. W, Duan J. Modern understanding for eighteen incompatible medicaments and nineteen medicaments of mutual restraint in TCM. Chin J Exp Tradit Med Formula. 2009;15(6):79–81.
  52. Tang J. L, Zhan S. Y, Ernst E. Review of randomised controlled trials of traditional Chinese medi-cine. BMJ. 1999;319(7203):160–1. [PMC free article: PMC28166] [PubMed: 10406751]
  53. Ulbricht C, Chao W, Costa D, Rusie-Seamon E, Weissner W, Woods J. Clinical evidence of herb-drug interactions. A systematic review by the natural standard researchcollaboration. Curr Drug Metab. 2008;9(10):1063–120. [PubMed: 19075623]
  54. Weng X. G, Nie S. Q, Huang L. Y. Determination of content changes of hypaconitine in preparations of aconite matching other herbs in "pinellia tuber, snake gourd fruit, fritillaria, Japanese ampelopsis root and common bletilla tuber counteract aconite" by HPLC. Chin Pharm J. 2004;39(1):57–9.
  55. World Health Organization. Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines. Geneva: World Health Organization; 1993.
  56. World Health Organization. Regulatory Situation of Herbal Medicines. A Worldwide Review. Geneva: World Health Organization; 1998.
  57. World Health Organization. Traditional and Modern Medicine, Harmonizing the Two Approaches. Manila: World Health Organization, Western Pacific Region; 2000a.
  58. World Health Organization. General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine. Geneva: World Health Organization; 2000b. WHO/EDM/TRM/2000.1.
  59. World Health Organization. Legal Status of Traditional Medicine and Complementary/Alternative Medicine: A Worldwide Review. Geneva: World Health Organization; 2001. WHO/EDM/TRM/2001.2.
  60. World Health Organization. WHO Guidelines on Good Agricultural and Collection Practices (GACP) for Medicinal Plants. Geneva: World Health Organization; 2003.
  61. World Health Organization. Report on the Second Consultation Meeting on Traditional and Modern Medicine: Harmonizing the Two Approaches. Manila, Philippines: World Health Organization; 2004.
  62. World Health Organization. WHO Monograph on Good Agricultural and Collection Practices (GACP) for Artemisia annua L. Geneva: World Health Organization; 2006.
  63. World Health Organization. WHO Guidelines for Assessing Quality of Herbal Medicines with Reference to Contaminants and Residues. Geneva: World Health Organization; 2007a.
  64. World Health Organization. WHO Guidelines on Good Manufacturing Practices (GMP) for Herbal Medicines. Geneva: World Health Organization; 2007b.
  65. World Health Organization. 2008. http://www​.who.int/dg​/speeches/2008/20081107/en/index.html WHO Congress on traditional medicine. Accessed August 2, 2009.
  66. Wu D, Lai S, Zhou L, editors. Further validation of the health scale of traditional Chinese medicine (HSTCM). Chin Med. 2009;4(1):8. [PMC free article: PMC2684103] [PubMed: 19405950]
  67. Xiao Z. J, Huang H, Zheng C. H, Zheng X. B, He Y. H. 2005The influence of Radix aconiti matched with Fritillaria to heart function of rat J Jiangxi TCM e117(2):50–1.
  68. Xue C. C. L, Hügel H. M, Li C. G, Story D. F. Efficacy, chemistry and pharmacology of Chinese herbal medicine for allergic rhinitis. Curr Med Chem. 2004;11(11):1403–21. [PubMed: 15180574]
  69. Xue C. C, Thien F. C, Zhang J. J, Da Costa C, Li C. G. Treatment for seasonal allergic rhinitis by Chinese herbal medicine: A randomized placebo controlled trial. Altern Ther Health Med. 2003;9(5):80–7. [PubMed: 14526714]
  70. Yue Q. Y, Bergquist C, Gerden B. Safety of St. John's wort (Hypericum perforatum). Lancet. 2000;355(9203):576–7. [PubMed: 10683030]
  71. Zhang G. J, Li G. L. Treatment of angina with combination of wutou, gualou and banxia. J Hebei TCM Pharmacol. 2009;24(1):46.
  72. Zhang A. L, Story D. F, Lin V, Vitetta L, Xue C. C. A population survey on the use of 24 common medicinal herbs in Australia. Pharmacoepidemiol Drug Saf. 2008;17(10):1006–13. [PubMed: 18816875]
  73. Zhou S. F, Zhou Z. W, Li C. G, Chen X, Yu X, Xue C. C, Herington A. 2007Identification of drugs that interact with herbs in drug development Drug Discov Today 12(15-16):664–73. [PubMed: 17706549]
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