Efficacy-oriented compatibility for component-based Chinese medicine
Acta Pharmacologica Sinica
Efficacy-oriented compatibility for component-based Chinese medicine
Jun-hua ZHANG 0
Yan ZHU 0
Xiao-hui FAN 1
Bo-li ZHANG 0 2
0 Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin 300193 , China
1 Pharmaceutical Informatics Institute, Zhejiang University , Hangzhou 310058 , China
2 Chinese Academy of Chinese Medical Science , Beijing 100700 , China
Single-target drugs have not achieved satisfactory therapeutic effects for complex diseases involving multiple factors. Instead, innovations in recent drug research and development have revealed the emergence of compound drugs, such as cocktail therapies and ?polypills?, as the frontier in new drug development. A traditional Chinese medicine (TCM) prescription that is usually composed of several medicinal herbs can serve a typical representative of compound medicines. Although the traditional compatibility theory of TCM cannot be well expressed using modern scientific language nowadays, the fundamental purpose of TCM compatibility can be understood as promoting efficacy and reducing toxicity. This paper introduces the theory and methods of efficacy-oriented compatibility for developing component-based Chinese medicines.
efficacy-oriented compatibility; component-based Chinese medicine; traditional Chinese medicine; multi-target drug
Human disease patterns have changed drastically in recent
decades. At present, chronic complex diseases such as
coronary heart disease, stroke, diabetes, cancer and chronic
obstructive pulmonary disease are common and drain large
amounts of healthcare resources. As a consequence,
medical purposes and models have been transformed. Recent
advances in health sciences have revealed accumulating
evidence of the limitations of the current one-drug-one-target
]. As a result, combination therapies,
such as multi-component drugs for multiple targets, are
gaining increasing attention and are considered as the next
paradigm in drug discovery[
]. For example, Caduet, a
combination of amlodipine and atorvastatin calcium, was approved by
the US Food and Drug Administration (FDA) in 2004 for the
treatment of hypertension and hypercholesterolemia.
Traditional Chinese medicine (TCM) prescriptions, which
are usually composed of several medicinal herbs, are typical
representative of compound medicines. After thousands of
years of clinical practice, a large number of TCM treatments
have been demonstrated to be of significant efficacy and
proven safety. In contrast to the simple addition of several
compounds to form a superpill, a TCM prescription follows
the principle of compatibility (peiwu) instead of simple stack
of herbs. The compatibility principles of TCM prescriptions
include considerations of herbal property (hot, cold, warm and
cool), herbal taste (acidic, sweet, bitter, pungent and salty),
and trend of drug action (meridian entry, up and down,
floatation and sinking, and open and close). Although TCM
theories are difficult to be expressed in modern scientific language,
the fundamental purpose of TCM compatibility is clear and is
the same as that of modern medicine: to increase efficacy and
Component-based Chinese medicine
The basic and most important questions closely related to
understanding and guiding the clinical practice of TCM are
the effective composition and the mechanism of action of a
TCM prescription. However, neither question has been well
elucidated due to their complexity. Moreover, it remains an
insurmountable challenge to clarify the active materials and
mechanisms of herbal decoctions or preparations made from
Chinese medicinal materials. Furthermore, the quality
standards of TCM preparations are not well established, especially
regarding the stability and homogeneity among batches. To
understand how TCM treats disease and to improve the
quality control level, the model and approach for research and
development (R&D) of new TCM drugs should be innovated.
TCM preparations, which are made from raw herbal slices
according to the compatibility theory of TCM, display certain
clinical effects. However, their effective materials and their
mechanisms of action and safety are not well established; the
quality control level is low; and dosages are based on
experience and ancient literature. By contrast, natural drugs are
mostly made from extractions of single herbs with a fixed ratio
of compounds. Research data regarding the effective
materials, mechanisms of action, dosages, efficacy and safety of
natural drugs are rich and available. Based on solid research
foundation, the quality control of natural drugs is well conducted
(Table 1). However, by neglecting the compatibility theory of
TCM in clinical experience, natural drugs lose the advantage
of compound medicines for complex diseases.
A new approach to develop modern Chinese medicine
should combine the strong points of both TCM and natural
drugs. Under the support of the National Key Basic Research
Project on key scientific problems of TCM prescriptions, we
previously proposed the concept of component-based Chinese
CCM is a type of modern Chinese medicine made from
standard components following the compatibility theory and
principles of TCM. The standard components are extractions
of medicinal herbs or TCM prescriptions with fixed
ingredients and ratios. Standard components, not clearly identified
compounds, are a group of active materials made using
standardized extraction, separation, and purification methods and
CCMs have the advantages of both TCM and natural drugs
(Table 1); they are guided by the theory and principle of
compatibility in TCM yet contain relatively stabile effective
substances and active mechanisms. In addition, CCMs are
characterized by standardized quality control and stability and
validated efficacy, safety and dosage. The active mode of CCMs
is multi-component for multiple targets/pathways involved
in complex disease pathology. Developing modern Chinese
medicine by the compatibility of standard components is
innovative in that it maintains the core advantages of TCM and
integrates the technology of modern drug design. The model
of CCM is suitable for developing new drug of small
prescription and for the secondary development of Chinese patent
There are many processes and techniques for developing
CCMs. Composing an ideal prescription is the key step, and
efficacy-oriented compatibility is a practical approach. The
principles and methods for efficacy-oriented compatibility are
The principles of efficacy-oriented compatibility are the
following: highlighting the primary effect, considering secondary
effects and reducing adverse effects. On the basis of clinical
experience, the preparation of standard components, analysis
of composition-activity relationships, and prescription
optimization should follow these principles. In addition,
efficacyoriented compatibility is ideal for developing small
prescriptions composed of no more than ten components.
Generally, efficacy-oriented compatibility should integrate
traditional experience with modern techniques. The
paradigm and related methods of efficacy-oriented compatibility
for CCM are described in Figure 1. The target disease and
its pathological stage are firstly defined. Then, data mining
methods are used to explore the targets and key nodes related
to the disease and to analyze potential effective prescriptions
and components. Using methods of network pharmacology
and high-throughput screening, the candidate prescription
is primarily revised and further evaluated by experimental
studies. The candidate prescription will then be optimized
according to the principles stated above, which is the key link
of efficacy-oriented compatibility. Finally, the optimized
prescription should be assessed by clinical trials (Figure 1). Some
of the available techniques are summarized below.
Along with the rapid development of science and technology,
significant progress has been made in the understanding of
life at the cellular and molecular levels. Targets associated
with certain diseases have been gradually discovered, and the
currently identified targets for disease treatment are
]. Potential targets associated with disease are mostly
reported in the scientific literature and biological databases.
For example, the most popular biomedical literature database,
MEDLINE/PubMed, currently contains more than 18
million literature abstracts, and more than 60 000 new abstracts
are added monthly. Similarly, chemical, genomic, proteomic
and metabolic data are collected in the MEDLINE database.
Developing in pace with the growth of biological databases,
the flourishing of bioinformatics, especially data mining
approaches, has changed the methods of target discovery[
Currently, text mining of literature databases and
microarray data mining are the two prevailing approaches to target
]. Text mining has been broadly applied to identify
disease-associated genes/proteins and to understand their
roles in diseases[
]. The systematic approach is a strategy that
selects targets through the study of diseases in whole
organisms using information derived from clinical trials and in vivo
animal studies. Researchers can identify disease-associated
networks and predict key nodes automatically by data
]. Although data mining is very useful for deriving
biological entities and insights from a large number of research
articles, it is a preliminary strategy that requires validation by
Database of standard herbal components
For drug discovery, historical experience is always significant.
Indeed, many TCM prescriptions have been used for
thousands of years. Thus, CCM should adequately utilize ancient
records and clinical experience. With innovations in analytic
technology and equipment, it becomes possible and easier to
determine the constituents of single herbs or prescriptions.
The ingredients of approximately 400 herbs that are
commonly used in TCM have been gradually identified. We have
established a component materials warehouse and database
for herbal components, which is a resource for developing
new prescriptions for multiple targets. Specifically, more than
20 000 standard herbal components have been extracted from
commonly used medicinal herbs and prescriptions.
In cooperation with the TCM research team at Zhejiang
University, we developed an in silico approach to predict
potential targets of herbal ingredients based on known
relationships between FDA-approved drugs and their targets.
The performance of predictive models was evaluated by
cross-validation and external datasets, which achieved good
predictive accuracy. The models were then applied to 10 339
TCM ingredients, resulting in 6670 predicted ingredient-target
relationships with high confidence. The TCM potential target
database (TCM-PTD) is now freely accessible online (http://
Network analyses of biological pathways and interactions
have revealed that much of the robustness of biological
systems is derived from the structure of the network[
with multiple ingredients aimed at multiple targets may show
better effects on the complex equilibrium of whole cellular
networks than drugs that act on a single target. Additionally,
systematic drug-design strategies should be more efficient
than simple combinations of several compounds.
Integrating network biology and polypharmacology holds the
promise of expanding the number of druggable targets. Advances
in these areas are creating the foundation of network
pharmacology for drug discovery[
]. Network analysis does not
preclude the identification of individual targets, yet the key
challenge facing the development of network pharmacology
is identifying a node or combination of nodes in a biological
network whose perturbation results in a desired therapeutic
]. Biological databases, data mining and databases of
herbal components provide the basic conditions for network
High-throughput screening (HTS)
Network pharmacological research can develop a candidate
prescription based on herbal components. The next step is to
optimize the components and proportions of the candidate
prescription. HTS is a well-established process in
discovery for pharmaceutical and biotechnology companies and
is increasingly applied to research in academia and medical
institutions. HTS has evolved into a mature discipline of
modern drug discovery. Tens of thousands to millions of samples
are tested in HTS campaigns for their ability to modulate
biochemical targets in cell-free assays and/or phenotypic or
targeted cell-based assays[
]. However, the application of HTS
for the identification of biologically active natural products,
such as TCM libraries, remains a relatively uncommon
The targets and cellular phenomena amenable to HTS
include nuclear receptors, G protein-coupled receptors
(GPCRs), ion channels, protein kinases, proteases, signaling
pathways, cell death mechanisms and others. For each
category of targets commonly subjected to HTS, natural product
modulators have been identified[
]. A strategy for the
production of high-quality fractionated libraries of Chinese herbal
formulas for HTS was first introduced by Liu et al[
]. A team
of US and Chinese co-investigators with expertise in TCM,
botany, chemistry and drug discovery has jointly established
a prototype library consisting of 202 authenticated
medicinal plant and fungal species that collectively represent the
therapeutic content of the majority of commonly prescribed
TCM herbal prescriptions. Initial screening targets have been
applied to preliminary evaluations of 3709 TCM fractions from
82 authenticated TCM species[
Developments in techniques for component characterizing,
biological evaluation and other screening methods under the
perspective of their applicability in natural product have been
described in an article by Zhu[
]. In particular, HTS is likely to
increase success in modern drug discovery from TCM.
Myocardial infarction (MI) is a typical polygenic disease.
Anti-platelet drugs, beta-blockers, angiotensin-converting
enzyme (ACE) inhibitors, and statins have been recommended
for clinical practice based on the results of randomized clinical
trials and their systematic reviews. However, most of these
conventional drugs are based on specific pathways, mainly a
single drug acting on a single target. This means that a patient
might need to take several drugs concurrently, which leads
to new problems, such as low adherence, high cost, and more
]. Thus, a new strategy for the management
of patients following MI is needed. The concept of ?polypill?
was developed approximately 12 years ago, with a compound
pill including several conventional drugs[
]. The Indian
Polycap Study showed that a polypill composed of
hydrochlorothiazide, atenolol, ramipril, simvastatin and aspirin had the
desired effects and was as safe as the individual pills[
polypill is a new concept in Western medicine, but it is not
new in TCM.
The Qi-Shen-Yi-Qi (QSYQ) pill, a type of polypill for
treating MI, is a CCM[
]. QSYQ is composed of extracts from 4
herbs: Radix Astragalus membranaceus (Huangqi), Radix Salvia
miltiorrhiza (Danshen), Panax notoginseng (Sanqi) and Lignum
Dalbergiae Odoriferae (Jiangxiang). These herbs constitute the
QSYQ pill based on efficacy-oriented compatibility principles.
Over the past several years, in vivo and in vitro studies have
revealed the integrated effects of QSYQ for MI, including
protection of cardiac muscle cells, prevention of cardiac
ischemiareperfusion injury via energy modulation, antagonized
ventricular remodeling, inhibition of the inflammatory reaction
and the progression of atherosclerosis, and stabilization of
atherosclerotic plaques through changes in histological
]. Recently, a network pharmacology study further
revealed the underlying multi-compound, multi-target and
multi-pathway mode of action (MOA) of QSYQ[
]. This study
evidentially confirmed the roles of the QSYQ component herbs
in the primary effect of treating MI: Huangqi serves as the
sovereign, Danshen as the minister, Sanqi as the assistant and
Jiangxiang as the courier[
Single-target drugs have showed only limited success for
multi-factor diseases, which is why the success rate of new
drugs is low despite careful and considerable efforts. The
fundamental problem may not be technological, but
philosophical: the wrong approach to drug discovery has been
followed. In the field of new drug R&D, ideas and methods are
undergoing innovation, and compound drug development is
becoming the cutting edge in new drug development. In
contrast to chemical drug development, which proceeds from the
laboratory bench to the clinical bedside, TCM preparations are
generated from clinical practice. The development of modern
or scientific Chinese drugs should begin with clinical
experience and classic prescriptions. The development of modern
science and technology provides powerful support for
developing new TCM drugs. One key point is that R&D of new
TCM drugs is inseparable from the theory of TCM, especially
the theory of prescription compatibility. Efficacy-oriented
compatibility is a practical mode for developing CCM, which
also needs further development in practice.
This work was supported by the National Key Basic Research
Program of China (2012CB518404); the Ministry of Education
of China-Program for Innovative Research Team (IRT1276);
and the New Century Excellent Talent of Ministry of
Education of China (NCET-13-0936).
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