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The Art and Science of
Traditional Medicine
Part 3: The Global Impact
of Traditional Medicine
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The content contained in this special, sponsored section was commissioned, edited, and published by the Science/AAAS Custom
Publishing Ofce. It was not peer-reviewed or assessed by the Editorial staff of the journal Science; however, all manuscripts have
been critically evaluated by an international editorial team consisting of experts in traditional medicine research selected by the
project editor. The intent of this section is to provide a means for authors from institutions around the world to showcase their
state-of-the-art traditional medicine research through review/perspective-type articles that highlight recent progress in this bur-
geoning area. The editorial team and authors take full responsibility for the accuracy of the scientic content and the facts stated.
Articles can be cited using the following format: [Author Name(s)], Science 350 (6262 Suppl), Sxx-Sxx (2015).
It is appropriate and timely that Chinese scientist Youyou Tu was
awarded half of the 2015 Nobel Prize in Physiology or Medi-
cine in recognition of her pioneering work on the antimalarial
artemisinin, extracted from Artemisia annua, an ancient herbal
remedy used to treat fever. This third issue in the Art and Science
of Traditional Medicine series features another time-honored
herb, ginseng. Also discussed are the systems and network
pharmacology of TCM, pharmacognosy and regulation of tradi-
tional medicine in Europe, and how these best practices can be
applied globally, but particularly in Africa. Attention garnered by
the Nobel award hopefully will generate interest in traditional
medicines from other parts of the world, including the Middle
East, the Indian sub-continent, and the Americas.
S53
Bill Moran, Global Director
Custom Publishing
bmoran@aaas.org
+1-202-326-6438
Ruolei Wu, Associate Director, Asia
Custom Publishing
rwu@aaas.org
+86-186-0082-9345
Editor: Sean Sanders, Ph.D.
Assistant Editor: Tianna Hicklin, Ph.D.
Proofreader/Copyeditor: Bob French
Designer: Amy Hardcastle
Contents
Tai-Ping Fan, Ph.D. (Guest project editor)
University of Cambridge, UK
Josephine Briggs, M.D.
National Center for Complementary & Alternative Medicine, NIH, USA
Liang Liu, M.D., Ph.D.
Macau University of Science & Technology, Macau SAR, China
Aiping Lu, M.D., Ph.D.
Hong Kong Baptist University, Hong Kong SAR, China
Jan van der Greef, Ph.D.
University of Leiden and TNO, The Netherlands
Anlong Xu, Ph.D.
Beijing University of Chinese Medicine, China
Editorial Team
Articles
S54 Ginseng: A panacea linking East Asia and North America?
S57 Pharmacognosy in the United Kingdom:
Past, present, and future
S59 Tra ditional herbal medicines in the European Union:
Implementing standardization and regulation
S61 Tra ditional African medicine:
From ancestral knowledge to a modern integrated future
S64 Tra ditional Chinese herbal medicine preparation:
Invoking the buttery effect
S66 Bridging the seen and the unseen:
A systems pharmacology view of herbal medicine
S69 Hypothesis-driven screening of Chinese herbs for
compounds that promote neuroprotection
S72 Mapping ancient remedies: Applying a network approach
to traditional Chinese medicine
S74 Drug discovery in traditional Chinese medicine: From
herbal fufang to combinatory drugs
S76 The polypharmacokinetics of herbal medicines
S79 The bioavailability barrier and personalized traditional
Chinese medicine
S82 Tra nsdermal treatment with Chinese herbal medicine:
Theory and clinical applications
S84 Acupuncture as a potential treatment for insomnia
ILLUSTRATION (FRONT) CHARLOTTE LOKIN
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According
to ancient Chinese
medical literature
and Korean history,
ginseng has been
used since around
2000 BCE. It has been regarded
as a very precious medicinal
plant, on par with poppy, aloe,
and garlic, the use of which
goes back to the same period
in other parts of the world. It
is not surprising that the name
Panax—meaning “all healing”
in Greek—has been applied to
this plant, because it has been
used to treat various diseases
from ancient times, and is also
recognized, especially in Asian
countries, as a health supplement
that can increase energy and
instill a sense of well-being. To
date, fourteen species belonging
to the Panax genus have been
identied, and three species
are widely circulated on the
global market: Panax ginseng
C.A. Meyer, cultivated mainly in
Korea and northeastern China;
Panax quinquefolius L. (American
ginseng), grown mainly in the
Canadian provinces of Ontario
and British Columbia and the
American state of Wisconsin; and
Panax notoginseng Burkill, found
in southern China (1).
History and use
P. ginseng is likely to have originated in Manchuria (now the
northeast part of China) and in the ancient Three Kingdoms
of Korea (2). The rst description of ginseng in the history of
traditional Chinese medicine appeared in the pre-Han era
(BCE 33–48), over 2,000 years ago. In 1713, the Royal Society
published a letter from Father Jartoux, a Jesuit missionary in
China, containing a description of ginseng’s botany, habitat,
and medicinal uses (3). P. quinquefolius was discovered by
American settlers in the mid-1700’s in New England. This plant
had long been used by the Native Americans, who valued the
root for its curative powers and life-enhancing capabilities.
Ginseng has purported use for the treatment of cancer, diabe-
tes, and cardiovascular dysfunctions, as well as for cognitive
enhancement with an apparently low rate of adverse effects.
In combination with other materia medica, P. ginseng and P.
notoginseng have been used in complex Chinese formulations
for treating angina pectoris (4, 5).
1Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
2School of Biological Sciences, University of Hong Kong, Hong Kong, China
3Davad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver,
Canada
4R&D Headquarters, Korea Ginseng Corporation, Daejeon, South Korea
5Department of Biology, Hong Kong Baptist University, Hong Kong, China
6World Health Organization Collaborating Centre for Traditional Medicine, Natural
Products Research Institute, Seoul National University, Seoul, South Korea
*Corresponding Authors: tpf1000@cam.ac.uk (T.P.F.), kims@snu.ac.kr (Y.S.K.)
Ginseng: A panacea linking East Asia
and North America?
Processing, chemistry, and metabolism
Most ginseng in today’s market is cultivated in the eld for
4 to 6 years. Ginseng is classied into three types, depending
on how it is processed after harvest: fresh ginseng (can
be consumed in its fresh state), white ginseng (dried after
peeling), and red ginseng, which requires special preparation
skills, such as steaming and drying under specic conditions.
Technology for the long-term storage of red ginseng was
developed by pioneers in ginseng manufacture, securing
the foundation for this form of the root. The process of
steaming stabilizes the ginseng with regard to metabolism,
and transforms the secondary metabolites into less polar
phytosteroids that are thought to be both more active in the
body and safer.
The active ingredients in ginseng include ginsenosides and
polysaccharides. Ginsenosides belong to the saponin family
and are divided into 20(S)-panaxadiols and 20(S)-panaxatriols,
depending on the dammarane skeleton and the number of
hydroxyl groups that can be substituted with other groups
(1). The biological activities of these phytosteroids have been
studied intensively with regard to their structure-activity rela-
tionships. Asian ginseng typically contains six types of ginsen-
osides: panaxadiols (Rb1, Rb2, Rc, and Rd) and panaxtriols (Re
and Rg1). In contrast, American ginseng contains high levels of
Rb1, Rd, and Re (6, 7).
Ginsenosides are extensively metabolized in the
gastrointestinal tract after oral administration (8), with sugar
moieties being removed to
generate the aglycones, 20(S)-
protopanaxadiol (aPPD), and
20(S)-protopanaxatriol (aPPT),
and the partially deglycosylated
ginsenosides. Since most native
ginsenosides are either poorly
absorbed in the intestines or
are quickly metabolized by
deglycosylation, oxidation,
and esterication in the
intestine or the liver, they
could be regarded as “pro-
drugs.” Thus, understanding
the pharmacokinetics and
pharmacodynamics of native
ginsenosides and their
metabolites is critical for their
clinical application.
Standardization
Currently, there are many
ginseng products on the
market and the quality control
of these commodities is of
paramount importance. Quality
control of ginseng extracts and
nished products is usually
based on the determination of
specic bioactive ginsenosides.
Although the international stan-
dard ISO 17217-1:2014 speci-
es minimum requirements and
test methods for ginseng seeds
and seedlings (9), ginseng
extract should also be standardized such that each batch
contains an acceptable concentration range of active ingredi-
ents to guarantee quality and efcacy from product to product.
Distinguishing between P. ginseng and P. quinquefolius, which
have similar chemical and physical properties but seemingly
different pharmacological activities, is a challenge. Recently,
all known ginsenosides were identied by metabolomics us-
ing high-performance chromatography/mass spectrometry
analysis, and this large data set was statistically analyzed. In a
targeted analysis, ginsenoside Rf was conrmed as a chemical
marker present in processed P. ginseng, but not in processed
P. quinquefolius (10).
Diverse pharmacological activities
via multiple mechanisms
Given the structural similarity between ginsenosides
and steroid hormones, we hypothesized that ginsenosides
function as receptor agonists, partial agonists, or antagonists
depending on the microenvironment. As shown in Figure 1,
ginsenosides act by binding to steroid hormone receptors,
such as androgen, estrogen, and glucocorticoid receptors,
to modulate gene expression (11–14). We have previously
reported that the dominance of Rg1 leads to angiogenesis,
whereas Rb1 exerts an opposing effect (15) through activation
of glucocorticoid (16) and estrogen (17) receptors. In addition
to their classic genomic effects, ginsenosides can also function
through transcription-independent, nongenomic activation
FIGURE 2. Metabolism of ginseng. Ginsenosides can be converted into their metabolites
that may contribute the majority of bioactivities by regulating the transportation and
metabolism of crucial substances in the human body. Metabolism mainly occurs in the
intestine and the liver by adenosine triphosphate (ATP)-binding cassette transporters (ABC
transporters), cytochrome P450 enzymes (CYPs), and others.
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
Authors:
Ran Joo Choi1,
Alice S. T. Wong2,
William Jia3,
Il-Moo Chang4,
Ricky N. S. Wong5,
Tai-Ping Fan1*,
Yeong Shik Kim6*
FIGURE 1. Schematic representation of genomic and nongenomic actions by ginsenosides.
Ginsenosides can act through genomic effects by binding to steroid hormone receptors,
such as androgen receptors (AR), estrogen receptors (ER), and glucocorticoid receptors
(GR), to modulate gene expression. On the other hand, nongenomic activities, such as
phosphoinositide 3-kinase/Akt (PI3K/Akt), adenosine monophosphate-activated protein
kinases (AMPKs), and endothelial nitric oxide synthases (eNOS) that occur outside the
nucleus can also be involved in the mechanisms of action (MOAs) of ginsenosides.
Ginsenosides are also implicated in ion channel regulation that includes the nicotinic
acetylcholine receptor that results in sodium ion (Na+) inux and the GABAA/glycine receptor
that conducts chloride (Cl–) ions. In addition, ginsenosides can be a regulator of microRNAs
(miRNAs) that modulate angiogenesis, apoptosis, cell proliferation, and differentiation.
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of signaling cascades, such as phosphoinositide 3-kinase/
Akt, adenosine monophosphate-activated protein kinase,
and calcium signaling that occurs outside the nucleus (18–23)
(Figure 1). Ginsenosides are also implicated in ion channel
regulation, including voltage-dependent and ligand-gated
ion channels, for the control of cardiovascular function
and hypertension (24–26). Recent developments have also
revealed ginsenosides to be an important regulator of
microRNAs (miRNAs) (27–30). Moreover, messenger RNA-like,
noncoding RNAs were identied in ginseng, suggesting that
it might exert a regulatory role through miRNAs and small
interfering RNAs (siRNAs) (31). Whether these small RNAs
could affect our body function awaits further investigation (32).
A number of studies have demonstrated that ginsenosides,
and especially their metabolites, interact with cytochrome
P450 enzymes (CYPs) and adenosine triphosphate (ATP)-
binding cassette transporters (ABC transporters, including
breast cancer resistance protein, BCRP) (33–36). Given the
fundamental roles of ABC transporters and CYPs in the
absorption, transportation, and metabolism of nutrients,
hormones, and environmental toxins, it is plausible that
ginseng may exert its wide-ranging biological effects and
health benets by modulating the transportation and
metabolism of vital substances in the human body (Figure 2).
Intriguingly, aPPD and aPPT are BCRP inhibitors and therefore
potential chemosensitizers (37). Ginseng root also contains
acidic polysaccharides that appear to play important roles in
immune modulation (38). In addition, ginseng polysaccharides
have shown antifatigue (39, 40) and antidiabetic (41) effects.
However, although numerous studies have been done in vitro
and in vivo, very few clinical studies exist.
Challenges and opportunities
Despite playing an important role as a health supplement
and medicine in East Asia for millennia, the clinical efcacy
of ginseng remains to be established through stringent
evidence-based validation. The synthesis of ginsenosides,
including the backbone and its glycosylated derivatives,
is extremely challenging. This bottleneck limits the
development of ginsenosides as drug candidates. Thus,
developing novel techniques for enriching bioac tive
components in ginseng should be a top priority. For
example, selective transformation of ginsenosides by
specic intestinal microbes may provide a new opportunity
for drug discovery. It is also an exciting prospect to obtain
the full genome sequence of ginseng root as a precursor to
manipulating the biosynthesis of specic ginsenosides and
realizing a “ginsenoside factory” (42–44). A high-throughput,
multidisciplinary approach should be developed to bring
new insight s into the molecular actions of ginsenosides and
how the multiple, distinc t signaling networks that it impacts
are interconnected. Finally, more robust clinical trials should
be designed and implemented. Only good clinical outcomes
can instill faith in patients and the general public with regard
to products derived from this time-honored treatment.
References
1. L. P. Christensen, Adv. Food Nutr. Res. 55, 1 (2009).
2. "A History of Ginseng," in Korean Ginseng, H. W. Bae, Ed. (Korea
Ginseng Research Institute, Republic of Korea, 1978), pp. 12–74.
3. J. H. Appleby, Notes Rec. Roy. Soc. 37, 121 (1983).
4. X. Zhao et al., Science 347, S38 (2015).
5. R. Liu et al., Science 347, S40 (2015).
6. N. Fuzzati, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
812, 119 (2004).
7. J. B. Wan et al., J. Sep. Sci. 30, 825 (2007).
8. L. W. Qi et al., Curr. Drug Metab. 12, 818 (2011).
9. International Standards Organization Online Browsing
Platform, ISO 17217-1:2014(en), "Traditional Chinese
Medicine—Ginseng Seeds and Seedlings—Part I: Panax
Ginseng C.A. Meyer”; available at https://www.iso.org/obp/
ui/#iso:std:iso:17217:-1:ed-1:v1:en.
10. H. W. Park et al., J. Ginseng Res. 38, 59 (2014).
11. Y. J. Lee et al., Mol. Cell Endocrinol. 133, 135 (1997).
12. Y. N. Lee et al., J. Steroid Biochem. Mol. Biol. 67, 105 (1998).
13 . Y. Yu et al., Cancer 109, 2374 (2007).
14. B. Cao et al., Int. J. Cancer 132, 1277 (2013).
15. S. Sengupta et al., Circulation 110, 1219 (2004).
16. K. W. Leung et al., J. Biol. Chem. 281, 36280 (2006).
17. K. W. Leung et al., Br. J. Pharmacol. 152, 207 (2007).
18. K. Shinkai et al., Jpn. J. Cancer Res. 87, 357 (1996).
19. K. W. Leung et al., FEBS Lett. 580, 3211 (2006).
20. K. W. Leung et al., FEBS Lett. 581, 2423 (2007).
21. T. T. Hien et al., Toxicol. Appl. Pharmacol. 246, 171 (2010).
22. K. W. Leung et al., Angiogenesis 14, 515 (2011).
23. Y. Liu et al., Cell Death Dis. 2, e145 (2011).
24. T. Kimura et al., Gen. Pharmacol. 25, 193 (1994).
25. S. Y. Nah, Front Physiol. 5, 98 (2014).
26. C. H. Lee et al., J. Ginseng Res. 38, 161 (2014).
27. K. O. Skaftnesmo et al., Curr. Pharm. Biotechnol. 8, 320 (2007).
28. L. S. Chan et al., Eur. J. Pharm. Sci. 38, 370 (2009).
29. N. Wu et al., Acta Pharmacol. Sin. 32, 345 (2011).
30. I. S. An et al., Oncol. Rep. 29, 523 (2013).
31. M. Wang et al., J. Integr. Plant Biol. 57, 256 (2015).
32. L. Zhang et al., Cell Res. 22, 107 (2012).
33. Y. Zhao et al., Planta Med. 75, 1124 (2009).
34. N. T. Chiu et al., Biopharm. Drug Dispos. 35, 104 (2014).
35. S. Deb et al., J. Steroid Biochem. Mol. Biol. 141, 94 (2014).
36. A. Kawase et al., J. Nat. Med. 68, 395 (2014).
37. J. Jin et al., Biochem. Biophys. Res. Commun. 345, 1308 (2006).
38. S. Kang et al., J. Ginseng Res. 36, 354 (2012).
39. J. Wang et al., Arch. Pharm. Res. 37, 530 (2014).
40. D. L. Barton et al., J. Natl. Cancer Inst. 105, 1230 (2013).
41. C. Sun et al., Food Funct. 5, 845 (2014).
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Acknowledgments
This work was supported by grants from the National Research
Foundation of Korea to Y.S.K. (MRC2009-93146) and the
Health and Medical Research Fund to A.S.T.W. (11121191)
For centuries, pharmacognosy has been in-
strumental in developing both conventional and
herbal medicines in Europe. Isolated phytochemicals
from natural sources have been the source for new pharma-
ceutical drugs and provided template chemical structures
for drug discovery. In recent years, natural products have
played a role in the development of approximately 50% of
approved new chemical entities (1). Moreover, the majority of
new small-molecule drugs of natural origin are derived from
terrestrial microbes, with others coming from higher plants,
marine organisms, and terrestrial animals (2). Juxtaposed with
natural product drug discovery is the development of herbal
medicines. These mixtures encompass medicinal plants that
may contain diverse and biologically active phytochemicals;
however, the active constituents of many herbal medicines are
unknown and evidence for efcacy is often limited. Therefore,
a major challenge for such medicines is quality control and
standardization. In the European Union (EU), movements to
harmonize the legislation surrounding traditional herbal medi-
cines have aimed to improve their safety and quality. However,
there are limitations and, in some respects, herbal medicines
are still less well-regulated compared to conventional medi-
cines. Although the use of herbal medicines in the United
Kingdom (UK) is popular, detailed knowledge of their phar-
macological and clinical effects is often lacking, as are data
on their pharmacokinetic and pharmacodynamic properties.
While EU legislation now provides standards for the quality
and safety of many herbal medicines, research to establish
the “science” behind their use is not progressing at the same
pace. Moreover, pharmacovigilance reporting practices could
be improved to assist practitioners in gaining a better under-
standing of appropriate uses and safety.
Herbal medicine use in the UK
Although herbal medicines are relatively popular (used
by 35% of the population in the UK), there is a general lack
of understanding about what herbal medicines are (or are
not); however, there is a broad perception amongst the
public that they are safe because they are “natural” (3). The
EU Directive (2004/24/EC) on Traditional Herbal Medicinal
Products (HMPs) introduced regulatory standards for herbal
medicines in April 2004. The directive requires EU member
states to implement regulatory arrangements for HMPs
that can be used without medical super vision and that have
evidence for traditional use (4). In response to this directive,
the UK’s Medicines and Healthcare products Regulator y
Agency (MHRA) launched the Traditional Herbal Medicines
Registration Scheme in 2005. Following a transition period to
allow HMP manufacturers time to comply with the directive’s
requirements, all such products intended for sale in the UK
require either a full marketing authorization or a traditional
herbal registration (THR). These regulations mean that THR
HMPs that are intended for minor conditions and are suitable
for self-diagnosis must meet the required standards for
quality and safety [with respect to European Pharmacopoeia
(EP) monographs and community herbal monographs
that are evaluated by the Committee on Herbal Medicinal
Products]. THR HMPs are required to have been used
medicinally for at least 30 years (prior to THR application),
with at least 15 years of use relating to the EU.
While these regulations have made advances in improving
the safety and quality of registered HMPs, several issues
still need to be addressed for the use of herbal medicines.
Evidence for “traditional use” currently takes the place of
hard scientic data from pharmacological tests and clinical
trials. Therefore, evidence for efcacy, the scientic or
pharmacological basis to explain the reputed activity, and
knowledge of the active constituents and their mechanisms
of action are limited for many herbal medicines. There are
relatively few robust clinical trials assessing efcacy for
the majority of herbal medicines. Clinical evaluation and
comparability are major issues for trials that investigate
inadequately authenticated or standardized herbal
medicines not subject to THR standards. Furthermore,
Regulation 3 of The Human Medicines Regulations 2012,
commonly referred to as the “herbalist exemption,” permits
unlicensed herbal remedies to be prepared and supplied
by an herbal practitioner to meet the needs of an individual
patient following a one-to-one consultation. Although this
practice enables herbal practitioners to meet the needs of
patient s by supplying tailored herbal medicines, a current
regulatory loophole allows anyone to practice herbal
medicine, regardless of their qualications or experience.
This clearly has implications for public health, from receiving
an appropriate diagnosis and treatment to dealing with the
safety and quality issues of the remedies that may occur with
unlicensed herbal medicines.
Herbal medicines used in the UK include traditional
European medicines such as sage (Salvia ofcinalis L.),
described in a 16th-century herbal by Gerard, who says it
is “singularly good for the head and brain and quickenethe
the nerves and memory,” and by Culpeper 50 years later,
who states that sage “also heals the memory, warming and
quickening the senses” (5). There are limited clinical trial data
to suggest that S. ofcinalis extracts can improve cognitive
function for healthy subjects and patients with dementia (5).
Although traditionally used to aid memor y, S. ofcinalis HMPs
are unlikely to gain THR status for cognitive disorders such as
dementia, because THR HMPs must comply with permitted
indications, which entail conditions that are suitable for
self-medication without the need for medical super vision.
However, S. ofcinalis THR HMPs are available in the UK to
Royal Botanic Gardens Kew, Richmond, Surrey, United Kingdom
*Corresponding Author: m.simmonds@kew.org
Pharmacognosy in the United Kingdom:
Past, present, and future
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
Authors:
Melanie-Jayne
R. Howes and
Monique S.J.
Simmonds*
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relieve some conditions that do not normally require medical
intervention, which include menopausal and cold symptoms
(based on traditional use). In addition to traditional European
herbal medicine, other prac tices of traditional herbal
medicine from a variety of cultures are increasingly being
used in the UK, including traditional Chinese medicine (TCM)
and those from Ayurvedic, African, and South American
traditions. Some of these are supplied under the herbalist
exemption and not controlled by THR regulations.
In 1864, the rst edition of the British Pharmacopoeia
(BP) was introduced, containing the ofcial monographs for
medicines in the UK. This collection of standards comprised
the required characteristics and tests for numerous herbal
medicines, including potentially toxic plants such as
aconite, Digitalis, and belladonna, as well as other naturally
derived remedies, such as puried ox bile and leeches (6).
Over the last 150 years, the development of conventional
pharmaceutical drugs has increased considerably, while
the use of herbal medicines in conventional “Western”
medicine has declined. This trend is reected in the current
BP, with fewer herbal medicine monographs included than
pharmaceutical drug monographs (7). However, with the
introduction of THR and HMP quality standard requirements,
the number of monographs for herbal medicines is
now increasing once again in the BP and European
Pharmacopoeia. Moreover, a higher number of species
monographs are included, reecting the incorporation of
different practices into UK medicine, such as TCM (e.g., Salvia
miltiorrhiza Bunge root and rhizome) and Ayurvedic medicine
(e.g., Withania somnifera (L.) Dunal root) (7).
Future directions
The introduction of the EU Directive (2004/24/EC) and THR
scheme in the UK have enabled progress on the safety and
quality control issues of many HMPs; however, the impact of
these regulations on safeguarding public health remains to be
determined. To evaluate these issues, thorough monitoring
of adverse responses to HMPs, either due to intrinsic (i.e.,
effects inherent in the plant itself) or extrinsic (i.e., effects
resulting from quality control issues such as adulteration or
substitution of the intended species) are essential. In general,
there is an underreporting (via pharmacovigilance schemes)
of adverse drug reactions (ADRs) by health care professionals
(HPCs) (8) as well as much variation between HCPs in the
reporting of ADRs (9). The importance of this type of reporting
is exemplied by St. John’s wort (Hypericum perforatum L.). In
this case, ADR reporting through pharmacovigilance schemes
led to the identication of several clinically important drug
interactions and potential safety issues (10). To promote
herbal medicines’ safe use, we recommend that HCPs improve
their knowledge of such remedies and encourage them to
report any ADRs and herb-drug interactions. Moreover, the
preparation and supply of unlicensed herbal medicines as
permitted under the herbalist exemption should also be
further scrutinized to improve the regulation of this practice
and address potential quality and safety issues, while
maintaining access to trained herbal medicine practitioners,
which many patients value.
Finally, the issue of efcacy needs to be addressed far
more robustly for many herbal medicines. More research
is needed to identify the active constituent(s) and their
modes of action, and to determine their polyvalent nature,
while understanding more about their pharmacokinetic and
pharmacodynamic properties (similar to the process for
conventional pharmaceuticals). It is essential to authenticate
and standardize HMPs in order to dene their safety, quality,
and efcacy standards and to enable clinical trial data to be
based on phytochemically characterized HMPs containing
standardized levels of active constituents. Meanwhile, the
fact that plants are incredible synthetic chemists and have
already provided numerous lead chemical structures (e.g.,
paclitaxel and docetaxel) for the development of conventional
pharmaceutical drugs, which may not have been discovered
via synthetic compound libraries, should not be ignored.
Plants have an important role in the future of medicine
and, whether they are used as herbal medicines or in drug
discovery programs, it is essential that they are cultivated from
sustainable sources and that their medicinal products are
designed to meet the appropriate standards for quality and
public health safety.
References
1. D. J. Newman, G. M. Cragg, J. Nat. Prod. 75, 311 (2012).
2. A. D. Kinghorn, L. Pan, J. N. Fletcher, H. Chai, Nat. Prod. Rep. 74,
1539 (2011).
3. MHRA, “Public Perception of Herbal Medicines”; available at
https://www.gov.uk/drug-safety-update/public-perception-of-
herbal-medicines.
4. Council Directive 2004/24/EC, O. J. L. 136, 85-90 (2004).
5. M-J. R. Howes, P. J. Houghton, Curr. Alzheimer Res. 9, 67 (2012).
6. British Pharmacopoeia (General Council of Medical Education
and Registration of the United Kingdom, London, 1864).
7. British Pharmacopoeia (The Stationery Ofce, London, 2014).
8. L. Hazell, V. Cornelius, P. Hannaford, S. Shakir, A. J. Avery, Drug
Saf. 36, 199 (2013).
9. G. Yamey, Br. Med. J. 319, 1322 (1999).
10. Committee on Safety of Medicines, Medicines Control Agency,
Current Problems in Pharmacovigilance 26, 6 (May 2000).
Medicinal plants have been used in Eu-
rope since ancient times. A variety of traditions for using herbal
preparations have developed throughout the current mem-
ber states of the European Union (EU), with a diverse set of
regulations developing throughout the 20th century. Recently
however, common legislation for the regulation of medicinal
products in the EU has emerged (1, 2). Providing a complete
set of data to satisfy EU regulatory requirements for bringing
herbal medicines to market has proven challenging because
many products have had a long history of different traditional
uses in the different states. A new legislative approach was
therefore developed in 2004 to harmonize the assessment of
and access to traditional herbal medicinal products (3). The
new legislation worked to combine scientic evaluation with
the large database of accumulated evidence collected over
many years of herbal medicine use.
Legal provisions for herbal medicine in the EU
The approval of medicinal products in the EU is linked to
the assessment of quality, safety, and efcacy by a regula-
tory authority. Basic denitions for herbal substances, herbal
preparations, herbal medicinal products, and traditional herbal
medicinal products have been provided in Community Direc-
tive 2001/83/EC, as amended by Directive 2004/24/EC (1, 2).
The legislation also describes the details of the documentation
requirements for market access for the three main catego-
ries of herbal medicines: (1) marketing authorization for new
herbal medicinal products based on a full set of new efcacy
and safety data; (2) marketing authorization for herbal medici-
nal products based on well-established use documented in
published literature (including clinical trials); and (3) registra-
tion for traditional herbal medicinal products, for which efcacy
is based on plausibility and long-standing use.
In order to harmonize scientic evaluation in the EU, the
Committee on Herbal Medicinal Products (HMPC) was estab-
lished at the European Medicines Agency (EMA) in London
in 2004 (3, 4). This scientic committee is composed of 28
members with one scientic expert from each member state.
Five co-opted members represent special elds of expertise:
pediatrics, general medicine, pharmacology, clinical phar-
macology, and toxicology. The core task of the HMPC is to
standardize herbal medicinal products and traditional herbal
medicine products in the EU by developing monographs and
list entries for herbal substances and their preparation. The es-
tablishment of monographs and other regulatory documents is
a fully transparent process starting with a public “call for data.”
A rapporteur is nominated by the HMPC and is responsible for
the evaluation of information provided from the public call for
data, the results of a systematic literature research in the public
domain, and market overviews provided by the member
states. A draft monograph is established while the scientic ev-
idence is evaluated and documented in an assessment report.
Scientic discussions in the Working Party on European Union
Monographs and List Entries (MLWP) and HMPC contribute to
revision of both documents, which are published for com-
ments together with a list of references. When a monograph
is nally adopted by the HMPC, the entire set of documents,
including an overview on the comments from the public con-
sultation, is made available on the EMA’s website. Since 2013,
the agendas and minutes of the plenary meetings of the HMPC
have also been published, and any interested party, applicant,
or citizen can access the work of the HMPC (5).
Developing standards for herbal medicines
When creating monographs for herbal medicines in the
EU, all of the available data is scientically evaluated to create
a unied view of the safety and efcacy of herbal substances
and their preparations. Monographs may include two varia-
tions: well-established use and/or traditional use.
Well-established use is based on approval of a product for
medicinal use in the EU market for at least 10 years. Efcacy
must be proven by at least one published successful clini-
cal trial together with published data that meet the further
requirements for efcacy and safety.
For traditional herbal medicinal product registration,
evidence for safety and efcacy are derived from the long-
standing use of a traditional medicinal product. The criteria
for a product’s acceptance includes demonstrating its use as
an herbal medicine for 30 years with at least 15 years of such
use in the EU. Additional safety data may be requested by a
national regulatory authority when deemed necessary. This
approach to approving traditional herbal medicines is only ap-
propriate for products that are very safe. Therefore, this avenue
is restricted to products that are administered orally, externally,
or by inhalation and that treat minor complaints. Ailments that
require a medical prescription, diagnosis, or supervision by a
medical doctor are excluded and traditional herbal medicines
must comply with provisions for over-the-counter medicines.
The application of monograph standards
Within the last 10 years, the HMPC has released approxi-
mately 130 monographs (for examples, see Table 1), 12 list en-
tries, 13 public statements, and about 40 guidance documents
(5). Only 25 monographs have been approved based on
well-established use. Public statements have been developed
when a monograph could not be drafted for reasons such as
1Department of Complementary and Alternative Medicines and Traditional Medicinal
Products at the Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany
2University of Athens, Faculty of Pharmacy, Division of Pharmacognosy and Chemistry of
Natural Products, Zografou Campus, Athens, Greece
*Corresponding Author: werner.knoess@bfarm.de
Traditional herbal medicines in
the European Union: Implementing
standardization and regulation
Authors:
Werner Knöss1* and
Ioanna Chinou2
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
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a lack of data or substance-specic
concerns. The guidance documents
address a broad set of issues related
to quality, safety, and efcacy to sup-
port further harmonization among
the member states.
The inventory of herbal substanc-
es that the monographs are intended
to represent currently has about 180
entries. Creating such support for the
safe and effective use of traditional
herbal medicinal products in the
EU is the primary goal of the HMPC.
The committee conducts a review of
the monographs every ve years in
order to provide a sustainable and
reliable system that represents the
current state of scientic knowledge.
More than 1,300 traditional herbal medicinal products have
been registered by the national regulatory authorities of the EU
member states. The registrations were granted for individual
applications that took the standards laid down in the legisla-
tion and described by the monographs into account. These
registered traditional herbal medicinal products cover a broad
spectrum of conditions, including coughs and cold, mood and
sleep disorders, gastrointestinal disorders, urinary tract/gyne-
cology disorders, and pain and inammation. Approximately
one-third of the approved products are composed of multiple
herbal preparations.
Globalization of traditional medicines
The ongoing globalization of traditional medicines has
brought with it a broad diversity of regulatory systems in dif-
ferent countries and regions. For example, there is a lack of in-
ternationally accepted denitions and standard requirements
for quality, safety, and efcacy. Different concepts have been
established to consider the particular characteristics of tradi-
tional medicines. Thus, companies face immense obstacles
when trying to gain access to different markets for their herbal
medicines. An international dialogue about scientic and regu-
latory issues is necessary to develop reasonable and adequate
requirements. Such a conversation should also address topics
such as translating indications into another cultural context or
therapeutic environment (e. g., an additional diet or a parallel
physical treatment), using material of a nonherbal origin, and
classifying herbal products.
The European legislation was primarily designed to deal with
traditional herbal medicinal products with a well-known origin
in Europe. However, the existence of therapeutic systems and
products from traditional Chinese medicine (TCM) or Ayurvedic
medicine within Europe has prompted the HMPC to address is-
sues related to non-European traditional medicines (6). A docu-
ment was released in the spring of 2014 that explained the
European regulatory framework and the options and limitations
for traditional products originating from non-European regions
(7). In addition, the HMPC has started a pilot project to create
monographs for the herbal substances used in Asian traditional
medicines, such as TCM and Ayurvedic medicine.
Conclusions
Harmonizing the process for evaluating and authorizing
traditional herbal medicines in the 28 member states of the EU
Traditional African medicine
(TAM) is characterized by a belief in
the supernatural as a cause of illness,
divination as a diagnostic tool, and the
ritualized use of a wide variety of plant-
and animal-derived agents in its treatment
(1). These are usually purchased from local
markets (Figures 1A and 1B) and remain
the primary source of health care for 80%
of both rural and urban populations (2).
In its strategy for 2014–2023, the World
Health Organization (WHO) encourages the development
and modernization of TAM as an integral part of emerging
health care systems (3). However, some of the more exotic
practices in TAM, which include the use of animal parts,
especially in the vodun (voodoo) religion in West Africa,
generate lurid headlines in the press and reduce the scientic
credibility of TAM. Herbs may be used as part of a regimen
in which physical characteristics (aroma, shape, color) and
attendant rituals (incantation, song) are more important than
pharmacological effects. However, effective strategies for
using TAM herbal knowledge are available, as exemplied
by a study on antimalarial plants used by traditional healers
in Nigeria (4). The demand for medicinal plants in Africa is
increasing dramatically due to population growth, resulting
in the risk of extinction of certain species and an increasing
likelihood of falsication of herbal materials. National
policies need to be developed to protect both patients
and endangered species (3) while protecting traditional
knowledge and conservation policies (5).
TAM as a source of therapeutic agents
It is necessary to understand how individual plants are used
in TAM in order to provide a context for exploration. Even
though they have been the source of new drugs, poisonous
species are rarely used for healing, since it is not possible to
accurately control the dose. Physostigma venenosum, the Cal-
abar bean, produces the alkaloid physostigmine (eserine), and
its derivative rivastigmine, used to treat Alzheimer’s disease. It
has no traditional medical use and was in fact administered as
an ordeal poison in Nigeria to those accused of witchcraft (1).
From an estimated African biodiversity of ~45,000 plant spe-
cies, only 5,000 have documented medicinal use (6). The list of
drugs provided by the African ora (Table 1) is short compared
with those from other traditional medical systems, suggesting
an unrivaled opportunity for the discovery of new drugs. Eth-
nobotanically directed approaches are more successful than
random selection, as demonstrated in studies using South
Traditional African medicine: From ancestral
knowledge to a modern integrated future
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
Properties Plant species Constituents and
therapeutics
Anticancer Catharanthus
roseus (L.) G. Don
(Apocynaceae);
Vincristine, vinblas-
tine, and others,
to treat leukemias,
Hodgkin’s lymphoma
Combretum
caffrum (Eckl. &
Zeyh.) Kuntze
(Combretaceae)
Combretastatins —
possible anti-angio-
genic; induces apop-
tosis in proliferating
endothelial cells
a2 adrenergic
antagonist
Pausinystalia
johimbe (K.Schum.)
Pierre ex Beille
(Rubiaceae)
Yohimbine, to treat
erectile dysfunction
and hypotension
Cholinesterase
inhibitor
Physostigma
venenosum Balf.
(Fabaceae)
Physostigmine
derivatives, to treat
myasthenia gravis
(neostigmine) and
Alzheimer’s disease
(rivastigmine)
Antihypertensive/
antipsychotic
Rauvola vomitoria
Afzel.
(Apocynaceae)
Reserpine‡ ,
occasionally used
clinically to treat
hypertension and
experimentally
to deplete
catecholamines
Anti-HIV Sutherlandia
frutescens (L.)
R. Br. (Fabaceae)
Antiretroviral effects
under investigation
Cardiotonic Strophanthus gratus
(Wall. & Hook.) Baill.
(Apocynaceae)
Ouabain (formerly
for heart failure),
used experimentally
to block Na-K-ATPase
Hallucinogenic Tabernanthe iboga
Baill.
(Apocynaceae)
Ibogaine, possible
treatment for
narcotic addiction
TABLE 1. Discoveries based on African medicinal plants.
Substance TU WEU
Harpagophyti radix
✓
Hyperici herba
✓ ✓
Pelargonii radix
✓
Valerianae radix
✓ ✓
Passiorae herba
✓
Ginseng radix
✓
Ginkgo folium
✓ ✓
TABLE 1. Selected examples of Committee on
Herbal Medicinal Products (HMPC) monographs
for herbal substances. TU, traditional use; WEU,
well-established use.
is an ongoing process. The legislation
and practices over the last decade
have demonstrated that it is possible
to standardize the scientic and regu-
latory evaluation of traditional medi-
cines. By considering their individual
characteristics and long-standing
uses, traditional medicines have been
made available to citizens in a more
regulated environment. HMPC mono-
graphs and monographs related to
the quality of herbs from the European
Pharmacopeia form the basis of the
regulation standards (8). Admittedly,
there are still challenging issues in the
EU surrounding specic topics such
as assigning well-established uses
and classifying certain products. The
EU’s legislation is not specic regarding how to distinguish be-
tween (herbal) medicinal products, food supplements, medical
devices, and cosmetics. On the global level, there is a need to
discuss different legal frameworks and to develop harmonized
solutions, which should take into account the specic indica-
tions for traditional medicines; the availability of marketed
products with adequate quality, safety, and efcacy; and the
means to provide reliable information to consumers and
health care experts for the use of herbal medicinal products.
References
1. European Parliament and EU Council, Directive 2001/83/
EC; available at http://ec.europa.eu/health/les/eudralex/vol-1/
dir_2001_83_cons/dir2001_83_cons_20081230_en.pdf.
2. European Commission Health and Safety Directorate-
General, "Marketing Authorisation, Notice to Applicants";
available at http://ec.europa.eu/health/les/eudralex/vol-2/a/
vol2a_chap1_201507.pdf.
3. European Parliament and EU Council, Directive 2004/24/
EC; available at http://ec.europa.eu/health/les/eudralex/vol-1/
dir_2004_27/dir_2004_27_en.pdf.
4. European Parliament and EU Council, Regulation (EC) No.
726/2004; available at http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:L:2004:136:0001:0033:en:PDF.
5. European Medicines Agency, "HMPC: Agendas, Minutes and
Meeting Reports"; available at http://www.ema.europa.eu/
ema/index.jsp?curl=pages/news_and_events/document_
listing/document_listing_000193.jsp&mid=WC0b01
ac0580028e96.
6. Committee on Herbal Medicinal Products, "HMPC Work
Programme for 2012–2015"; available at http://www. ema.
europa.eu/docs/en_GB/ document_ library/Work_
programme/2011/12/WC500119957.pdf.
7. Committee on Herbal Medicinal Products, "Questions & Answers
on the EU Framework for (Traditional) Herbal Medicinal Products,
Including Those from a ‘Non-European’ Tradition"; available at http://
www.ema.europa.eu/docs/en_GB/ document_library/ Regulatory_
and_procedural_guideline/2014/05/WC500166358.pdf.
8. European Pharmacopeia, 8th Ed. (European Directorate for
the Quality of Medicines, Strasbourg, 2014).
Acknowledgments
The views expressed in this article are the views of the authors
and may not be understood or quoted as being made on behalf
of or reecting the position of the European Medicines Agency
or any of its Committees or Working Parties. The authors state no
conict of interest. The data and gures provided are based on
data available in September 2014.
Authors:
Joseph Kahumba1,
Tsiry Rasamiravaka2,3,
Philippe Ndjolo Okusa4,
Amuri Bakari1,4,
Léonidas Bizumukama5,
Jean-Baptiste Kalonji6,
Martin Kiendrebeogo7,
Christian Rabemenantsoa3,
Mondher El Jaziri2,
Elizabeth M. Williamson8*,
Pierre Duez4*
1Laboratoire de Pharmacognosie, Université de Lubumbashi, Lubumbashi, Democratic
Republic of the Congo
2Laboratoire de Biotechnologie Végétale, Université Libre de Bruxelles, Belgium
3Laboratoire de Biodiversité et de Biotechnologie, Institut Malgache de Recherches
Appliquées (IMRA), Antananarivo, Madagascar
4Department of Therapeutic Chemistry and Pharmacognosy, Université de Mons
(UMONS), Mons, Belgium
5Department of Chemistry, Université du Burundi, Bujumbura, Burundi
6Laboratoire de Pharmacie Galénique et Analyse des Médicaments, Université de
Lubumbashi, Lubumbashi, Democratic Republic of the Congo
7Laboratoire de Biochimie et Chimie Appliquées, Université de Ouagadougou,
Ouagadougou, Burkina Faso
8School of Pharmacy, University of Reading, Whiteknights Campus, Reading, United
Kingdom
*Corresponding Authors: e.m.williamson@reading.ac.uk (E.M.W) and pierre.duez@
umons.ac.be (P.D.)
‡Reserpine had, however, been isolated 2 years earlier from Rauvola
serpentina (L.) Benth. ex Kurz, found in India.
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African Cape ora (7) and African plants that contain ef fec-
tive antihyperglycaemic agents (8).
Parasitic infections are a major cause of death in Africa,
and TAM herbs are widely used to treat them. However,
like many diseases in developing countries, these diseases
remain underresearched as they do not promise a good
commercial return on investment. Never theless, new lead
antiprotozoal compounds have emerged from herbs used
in TAM to treat malaria, and include cowaxanthone (from
Garcinia cowa), which has comparable antiplasmodial
activity to pyrimethamine (9), and cryptolepine (from
Cryptolepis sanguinolenta) (10). Clinical trials of Nauclea
pobeguinii extracts have also shown promising results in
the treatment of malaria (11). There are still no vaccines for
leishmaniasis, and the toxicity of antimony- and pentamidine-
The alarming incidence of bac terial multidrug resistance
to antibiotics requires an urgent search for new antibacteri-
als. The expression of virulence factors in many pathogens
requires the full activation of quorum sensing (QS) processes:
cell-to-cell bacterial communication mechanisms that detect
critical cell numbers by producing and recognizing diffusible
signal molecules termed “autoinducers.” The compounds
coordinate the expression and regulation of virulence fac-
tors, biolm formation, and motility. QS presents a promis-
ing series of targets to antagonize virulence in pathogens
and/or disturb biolm formation. For example, catechin and
naringenin inhibited the production of virulence factors in
Pseudomonas aeruginosa PAO1, a consequence of reduced
expression of QS- (lasB and rhlA) and QS-regulatory (lasI,
lasR, rhlI and rhlR) genes (14, 15). Recently, the Malagasy
species Dalbergia trichocarpa, traditionally used to treat
diarrhea and laryngitis, was shown to inhibit a wide variet y of
virulence factors in P. aeruginosa PAO1; its constituent cou-
marate esters interfere with the QS system’s rhl and las gene
expression (16). Extracts of Kigelia africana, used topically on
wounds and abscesses, have been shown to inter fere with
the response of bacteria to autoinducers, and to modulate
their synthesis in Chromobacterium violaceumand Agrobac-
terium tumefaciens (17).
Conclusions
TAM currently supports the medical needs of millions of
Africans. Based on experience gained from other traditional
medicine systems, it s modernization and integration with
conventional medicine may offer a
new and holis tic view of health care,
contributing to better universal health
coverage in Africa, as advocated by
the World Health Organization. This
remains quite a challenge, as depic ted
in Figure 2, despite the rich source of
new active compounds to be found in
African ora. This ora is ripe for explo-
ration, as long as traditional medical
uses and methods of administration are
interpreted with caution, and the right s
of local people and the environment
are respected.
References
1. D. T. Okpako, Trends Pharm. Sci. 20,
482 (1999).
2. O. M. J. Kasilo, J. M. Trapsida, C. N.
Mwikisa, P. Lusamba-Dikassa, The
African Health Monitor 14, 7 (2010).
3. WHO Traditional Medicine Strategy:
2014–2023 (World Health
Organization, Geneva, 2013).
4. I. P. Dike, O. O. Obembe, F. E.
Adebiyi, J. Ethnopharmacol. 144,
618 (2012).
5. WHO Regional Ofce for Africa,
“Intellectual Property Approaches to
the Protection of Traditional Knowledge
in the African Region”; available at
http://www.aho.afro.who.int/en/ahm/
issue/13/reports/intellectual-property-
approaches-sprotection-
traditional-knowledge-african.
6. M. F. Mahomoodally, Evid. Based. Complement. Alternat. Med.
2013, 617459 (2013).
7. C. H. Saslis-Lagoudakis et al., Proc. Natl. Acad. Sci. U.S.A. 109,
15835 (2012).
8. R. N. Ndip, N. F. Tanih, V. Kuete, in Medicinal Plants Research in
Africa (Elsevier, London, UK, 2013), pp. 753–776.
9. J. Bero, M. Fréderich, J. Quentin-Leclercq., J. Pharm. Pharmacol.
61, 1401 (2009).
10. L. F. Rocha e Silva et al., Phytomed. 20, 71 (2012).
11. K. Mesia et al., Planta. Med. 78, 853 (2012).
12. M. Wink., Molecules 17, 12771 (2012).
13. D. Musuyu Muganza et al., J. Ethnopharmacol. 141, 301 (2012).
14. O. M. Vandeputte et al., Appl. Environ. Microbiol. 76, 243
(2010).
15. O. M. Vandeputte et al., Microbiology 157, 2120 (2011).
16. T. Rasamiravaka et al., Microbiology 159, 924 (2013).
17. H. Y. Chenia, Sensors 13, 2802 (2013).
FIGURE 2. Africa’s challenge: A future modern health care system integrating
traditional medicine.
FIGURE 1B. A traditional
medicine stall in Lubumbashi,
Democratic Republic of the
Congo. Key: (1) Pterocarpus
angolensis D.C. Stem
(hemorrhoids, nappy/diaper
rash), (2) Solanum incanum L.
fruits (gonorrhea and hernia),
(3) Shell from Lualaba River
(welding fontanel), (4) Tortoise
shell (burns treatment), (5)
Albizia adianthifolia stem bark
(aphrodisiac and perianal swelling
treatment), (6) Diplorhynchus
condylocarpon (Müll.Arg.) Pichon
stem (abdominal pain, wound
healing), (7) Cassia sieberiana
D.C. roots (hemorrhoids, skin
irritation), (8) Mucuna poggei
Taub seeds (nappy/diaper rash;
analgesic in pelvic pain).
FIGURE 1A. A traditional
medicine stall in Madagascar.
Key: (1) Eucalyptus citriodora
leaves (respiratory antiseptic),
(2) Aloe vahombe leaves
(immunostimulant), (3)
Cedrelopsis grevei bark (tonic,
aphrodisiac), (4) Zea maïs
(silk) (diuretic), (5) Aphloia
theiformis leaves (antipyretic),
(6) Combretum albiorum seeds
(deworming), (7) Curcuma
longa rhizome powder (against
jaundice), (8) Raventsara
aromatica bark (respiratory
antiseptic, antibiotic), (9) Mollugo
nudicaulis leaves (antitussive),
(10) Tallow molded into balls.
based drugs means that interest in plant-derived leads for
potential antileishmanial drugs remains high. These include
chelerythrine derivatives (from Garcinia lucida), gibbilimbol B
(Piper malacophyllum), warif teine (Cissampelos sympodialis),
and avonoids from Baccharis retusa and Kalanchoe
pinnata (12). African trypanosomiasis (sleeping sickness)
is usually fatal if left untreated, but Momordica balsamina,
Securidaca longipedunculata, and Quassia africana have
yielded compounds with potent activity (13). Medicinal
plants also contain compounds with activities unrelated to
traditional use, which must be borne in mind and may also
be exploited. Indeed the antileukemia Vinca alkaloids were
discovered serendipitously when the Madagascar periwinkle
Catharanthus roseus was being investigated for its anti-
diabetic properties.
A
B
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The metaphor of
the “buttery effect”—in
which the proverbial
buttery’s apping wings
contribute to a tornado across the
other side of the globe—is based
in chaos theory and encapsulates
the concept that a small change at
one place in a complex system can
have large effects elsewhere (1).
Such an effect could be construed as
contributing to the unique nature of
Chinese herbal medicines (CHMs),
whereby several specic variables
that initially may have minor effects
can have a signicant downstream
impact on the quality, potency, and
therapeutic efcacy of the nal
product (2). Two of these factors are
the pharmaceutical practices of paozhi
processing of herbal drugs and the
formation of hot-water decoctions
from single or multiple herbal drugs
(formulae) based on ancient tradition.
These two factors act on the chemical
composition and biological activity
of the resulting tang decoction that is
nally consumed (3, 4).
The art of paozhi
According to traditional Chinese medicine (TCM) theory,
paozhi processing transforms raw herbal drugs into “decoc-
tion pieces,” thus instilling them with the desired properties
for their medical application, including improved avor and
detoxication or alteration of their therapeutic efcacy. Paozhi
encompasses techniques such as cutting, crushing, calcin-
ing, or frying with or without liquid adjuvants such as vinegar
or honey (3). A prominent example is the highly toxic crude
root of Aconitum carmichaelii (Fuzi) which, after detoxication
by paozhi processing, is incorporated into numerous TCM
formulae used to treat joint pain and rheumatic disease (5, 6).
Also, different kinds of decoction pieces can be derived from
the same raw material by processing in different ways. For ex-
ample, the Chinese pharmacopeia describes four different de-
coction pieces that may be derived from raw rhizomes of the
species Coptis (7). These pieces, from the same source, have
distinct activity and different sites of action within the human
body (Figure1). Despite its long tradition, it is only recently
that the effects of paozhi have been systematically studied. The
current understanding is that paozhi processing can alter the
qualitative and quantitative chemical composition of herbal
materials and can thus impact the nal pharmacological or
toxicological properties of the decoction pieces (3).
Chinese herbal decoctions
TCM formulae are typically composed of two or more
processed herbal drugs that are jointly decocted. Traditional
decoctions (tang) are prepared by repeated boiling of decoc-
tion pieces in water for 1 or more hours. The method may also
require soaking in cold water before heating, or the introduc-
tion of single herbal components later in the process. The
composition of the tang decoction can be changed by simple
actions such as an initial soaking in cold water, which initiates
innate enzymatic activity resulting in the alteration of chemical
1Trinity College Dublin, School of Pharmacy and Pharmaceutical Sciences, and Trinity International
Development Initiative, Trinity Biomedical Sciences Institute, Dublin, Ireland
2University of Vienna, Department of Pharmacognosy, Vienna, Austria
3Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, Shanghai, China
4University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Münster, Germany
*Corresponding Author: jandirk.sendker@uni-muenster.de
Traditional Chinese herbal medicine preparation:
Invoking the butterfly effect
FIGURE 1. According to TCM theory, paozhi processing yields decoction pieces with
variable therapeutic properties (3, 7).
composition, as demonstrated by the formula of Fuzi Xiexin
Tang (FXT) (8). In addition, studies of the simple two-herb
formula Danggui Buxue Tang (DBT), composed of Astragalus
membranaceus root and Angelica sinensis root, demonstrate
how multiple parameters like decoction time, initial tempera-
ture, paozhi processing, or the ratio of the two herbal ingredi-
ents may impact the chemical composition and activity of the
resulting tang decoction (Figure 2) (4, 9–11). In particular, in the
examples of DBT and FXT, as well as other studies, the practice
of joint decoction of herbal materials itself was found to affect
the properties of the nal product. With DBT, joint decoction
showed a signicantly improved cardioprotective effect on
isolated rat hearts (12) and osteoblast differentiation (13) when
compared to a mixture of individually prepared decoctions of
Angelica and Astragalus roots. Signicantly, the concentrations
of some of DBT’s phytochemicals were found to be increased
by 10% to 4,900% in the same studies due to coextraction.
It was concluded that the observed synergism results from
physicochemical interactions between the chemical constitu-
ents of both herbal ingredients. Such interactions have been
observed in several studies with other formulae (see 8, 14–16).
Physicochemical interactions
Physicochemical interactions may affect the solubility of
phytochemicals in simpler environments than a Chinese
tang decoction. It has been observed that ubiquitous herbal
constituents like sugars, amino acids, or small organic acids
can function singly or in combination as natural deep eutectic
solvents, which are able to dissolve phytochemicals and bio-
logical macromolecules up to 460,000-fold better than water
(17). The solubility of phytochemicals in water itself can also be
affected by the presence of other small organic molecules, as
exemplied by hypericine from St. John’s wort, the solubility
of which increases 120-fold in the presence of tannins (18). In
contrast, a reduction in the solubility of different toxic alkaloids
was observed in the presence of rhubarb root, a process be-
lieved to be linked to the formation of insoluble sediments (8).
An exciting new nding is that traditional paozhi process-
ing techniques may also augment a decoction’s therapeutic
efcacy based on physicochemical interactions. Preparing DBT
with Angelica sinensis root that has been processed with rice
wine according to the traditional protocol not only resulted in
modied concentrations of Angelica phytochemicals, but also
signicantly increased the concentrations of the observed As-
tragalus phytochemicals; the qualitative phytochemical chang-
es were accompanied by an increase in estrogenic and osteo-
genic activity (19). Some of these physicochemical interactions
have been recently modeled using ferulic acid, a constituent
of Angelica sinensis. The acid increased the concentrations of
Astragalus phytochemicals and displayed a dose-dependent
effect on the estrogenic and osteogenic activity of a decoction
from Astragalus roots, but only when added before the decoc-
tion process. Ferulic acid alone was completely inactive in
these models (20). This example demonstrates that such com-
plex physicochemical interactions may account for synergistic
effects on the biological activity of CHMs and thus contribute
to other possible synergisms that may occur due to pharmaco-
kinetic or pharmacodynamic effects (14).
Conclusions
Modern scientic study of TCM is leading to an increased
understanding of the complex interactions occurring between
herbal components during the processing and extraction of
these medicines. The examples given here indicate that the
evolution of these ancient processes over millennia may actu-
ally have improved the therapeutic efcacy and safety of the
resulting tang decoctions. The increased knowledge of these
relationships provides support for the proper use of traditional
procedures in the preparation of CHMs.
As discussed above, subtle changes in the complex produc-
tion chain of CHMs can inuence
the composition and efcacy of tang
decoctions through specic interac-
tions between their constituents. The
extent of such interactions may be
inuenced by a single detail like the
paozhi impact on one ingredient,
thus invoking a buttery effect.
Unlike the proverbial buttery,
however, the application of modern
scientic methodologies allows the
source of the disruption to be traced
by correlating the chemical prole
(metabolome) of the herbal prepara-
tion with its bioactivity. This approach
can also effectively aid the identica-
tion of chemical features that indi-
rectly inuence an herbal medicine’s
therapeutic efcacy (21). Knowledge
about the role of particular herbal
ingredients or phytochemicals within
a CHM is a prerequisite for the devel-
opment of meaningful quality control
assays, and thus a requirement for
the international registration of TCM
products. Without fully understand-
ing the subtle contributing factors,
FIGURE 2. Selection of factors affecting the chemical composition of a tang decoction.
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
Authors:
Helen Sheridan1,
Brigitte Kopp2,
Liselotte Krenn2,
Dean Guo3,
Jandirk Sendker4*
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modernization of TCM could negatively impact the unique
properties and therapeutic activity of these medicines. Modern
technologies and international collaborations will provide an
excellent platform to fully explore and elucidate the complex
interactions in herbal medicines in the future and thus aid the
development of modernized CHMs that maintain the thera-
peutic properties of their ancestors.
References
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(2009).
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2014 (2014), doi: 10.1155/2014/608721.
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2011 (2011), doi: 10.1093/ecam/nen085.
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115, 483 (2008).
17. Y. Dai, J. van Spronsen, G. J. Witkamp, R. Verpoorte, Y. H. Choi,
Anal. Chim. Acta 766, 61 (2013).
18. A. Nahrstedt, V. Butterweck, J. Nat. Prod. 73, 1015 (2010).
19. T. T. X. Dong et al., J. Agric. Food Chem. 54, 2767 (2006).
20. K. Y. Z. Zheng et al., Planta Med. 80, 159 (2014).
21. H. Sheridan et al., J. Ethnopharmacol. 140, 482 (2012).
The human body functions as a dynamic
ecosystem consisting of innumerable interact-
ing systems, creating emerging properties
and synergetic effects and extending beyond
the physical barriers of the human organism,
encompassing interactions with the environ-
ment. Understanding the human organism in
its full complexity requires consideration of
its different levels of organization (Figure 1,
left) (1).
Medical questions regarding how a disease develops and
how to prevent and intervene are amenable to a system-
oriented paradigm in which interventions include multitarget
pharmacological strategies that can inuence processes across
systems (2, 3).
Although Western medicine has provided a very success-
ful disease management system based on intervention at a
single target, further improvements will rely heavily on new
diagnostic tools to differentiate between disease subtypes and
individual biological patterns.
Recognition of the uniqueness of each human entails dif-
ferentiation at higher levels of organization, which requires
a systems approach and expanded diagnostic insights (4). A
better understanding of the biology and the inuence of multi-
target approaches on regulatory pathways could provide new
perspectives for system-level interventions (5). Understanding
system resilience to a multitude of environmental stressors
will shed light on personalized health and prevention options
within a biopsychosocial context.
In medical plant research, isolates of single components are
primarily used, which does not reveal the synergetic proper-
ties and full impact of the natural product. This was elegantly
demonstrated in studies of Berberis fremontii (Frémont’s
mahonia), which showed that the antimicrobial effects of the
bioactive compound berberine were enhanced >100-fold
when combined with an inactive component, 5’-methoxyhyd-
nocarpin, isolated from the same plant (6). Reverse pharma-
cology, wherein a traditional preparation is taken as a starting
point, holds promise for studying the synergetic nature of
herbal medicine (5), especially when combined with subtyping
based on modern 'omics technologies. Combining phenome-
nological descriptions of a system from TCM with experimental
data can provide a top-down guide that includes a wealth of
information and may even facilitate novel insights.
Bridging the seen and
the unseen: A systems
pharmacology view of
herbal medicine
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
Authors:
Yan Schroën1,2,
Mei Wang1,3,
Herman A. van
Wietmarschen1,4,
Renger
Witkamp5,
Thomas
Hankemeier6,
Tai-Ping Fan7,
Jan van der
Greef1,3,4,6*
DXXK as an example
An example of the application of a systems pharmacology
perspective in multitarget pharmacology research can be
illustrated by Diao Xin Xue Kang (DXXK), the rst traditional
Chinese herbal medical product registered in Europe and pro-
duced in China according to the European Traditional Herbal
Medicinal Products legislation. DXXK is an extract of rhizomes
from Dioscorea nipponica Mankino, a plant from the Diosco-
reaceae (yam) family. Over 300 papers have been published
on the extract’s pharmacology, safety, and mechanisms of ac-
tion, and DXXK has been subjected to phase 1, 2, and 3 clinical
trials with an estimated 16,000 patients enrolled (7). The main
focus in these studies has been its use in the treatment of
myocardial dysfunction, an indication included in the TCM
description of the plant.
To obtain a systems view of the biochemical and
functional effects of DXXK, pharmacological studies have
examined various biochemical pathways, ranging from
molecular to organ-level assessments. Analysis of DXXK’s
phytopharmacological constituents revealed that its bioactivity
could be attributed to a group of steroidal saponins, namely
dioscin, diosgenin, prosapogenin A, and prosapogenin C
(8–12). Saponins inuence oxidative stress (12, 13), which
is a major risk factor for vascular endothelial cell apoptosis,
a process that is implicated strongly in the pathogenesis of
cardiovascular disorders (14, 15). Steroidal saponins also
exhibit vasodilator and protective effects on human vascular
endothelial cells (16, 17). Clinical studies have shown that
these saponins have protective effects against hyperlipidemia,
including inhibition of platelet aggregation and reductions in
cholesterol and triglyceride levels (18–20).
Studies at the cellular level have revealed that DXXK affects
the renin-angiotensin-aldosterone system in a manner that is
consistent with its antihypertensive effects (21). At the organ
level, the phytoestrogen diosgenin, which is also found in
DXXK, acts as a vasodilator and modulates vascular smooth
muscle function by regulating cell viability, migration, and cal-
cium homeostasis (22, 23). Recent studies have revealed that
the signicant anti-inammatory effect may be attributed to
its inhibitory effect on the NF-κB/COX-2 pathway and relevant
inammatory mediators including prostaglandin 2, nitric oxide,
tumor necrosis factor a, interleukin (IL) 1β and IL-6 (24).
In TCM, DXXK is used to treat a variety of conditions,
including myocardial dysfunction, atherosclerosis, hyperten-
sion, migraine, and muscle spasms. From a Western perspec-
tive, these disparate applications suggest that there may be
1Sino-Dutch Centre for Preventive and Personalized Medicine, Zeist, the Netherlands
2Oxrider, Education and Research, Hilvarenbeek, the Netherlands
3SU BioMedicine BV, Utrechtseweg, Zeist, the Netherlands
4TNO, Department of Microbiology and Systems Biology, Zeist, the Netherlands
5Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
6Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden
University, Leiden, the Netherlands
7Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
*Corresponding Author: jan.vandergreef@tno.nl
FIGURE 1.
An example
of systems
pharmacology
in herbal
medicine.
Left, a systems
view of human
biology, with
selected effects
of Diao Xin Xue
Kang (DXXK).
Right, the four
traditional
Chinese
medicine (TCM)
symptom
clusters that
are the main
intervention
targets for
DXXK in China
are illustrated
for angina
pectoris.
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shared regulatory pathways related to these conditions. In a
more general sense, TCM offers attractive ways to generate a
systems view on interdisease relationships owing to its unique
knowledge of symptom patterns, which can be translated into
Western concepts.
However, some important and intrinsic characteristics
underlying the complexity of the TCM concepts can be lost
in translation. Elucidating this missing information can build
a bridge between Western and Chinese medicine, providing
insights into large-scale organization (Figure 1, left). In par-
ticular, symptom relationships can help to bridge Chinese and
Western perspectives on disease states (Figure 1, right) and
can point to associations among regulatory pathways, a likely
level at which major synergetic effects can be uncovered.
Where East meets West
Closer examination of points of interconnectedness be-
tween Chinese disease subtypes and Western pharmacology
suggests that key elements in DXXK bioactivity involve the
musculature. This is consistent with DXXK’s ability to induce
relaxation of vascular muscles (25–28) and reduce stress-re-
lated tension in intestinal, cardiac, and skeletal muscles (the
latter involving the neck), as well as to reduce muscle spasms
in the lower back and legs (29). Interestingly, Leino-Arjas et
al. demonstrated a relationship between cardiovascular risk
factors such as atherosclerosis and lower back pain (30).
A dynamic systems view of the effects of DXXK on
cardiovascular disease progression is illustrated schematically
in Figure 2. A healthy system can respond to and exchange
information with its environment efciently. Stressors can
move a resilient system into a temporary state of allostasis.
Systems should return to homeostasis when the offending
stressors have been alleviated. The development of an
allostatic load leads to the loss of ability to cope with stressors
within the boundaries of a healthy condition (31), resulting in
a stable angina. Eventually, the system may fall into a state in
which it is unable to return to normal stasis conditions, even
after direct stressors have been alleviated. That is, a person
may develop unstable angina and even cardiac infarction
(Figure 2, left). Clinical observations and phase 3 clinical
study ndings suggest that DXXK may prevent the system
from progressing toward the diseased state (Figure 2, right)
(32). The multitude of pharmacological effects related to the
relaxation of vascular muscles observed with administration
of DXXK can be explained by a putative systems-level
organization change wherein an underlining dysfunctional
regulatory process may be inuenced. If so, then DXXK may
be achieving an improvement in the muscle function at a
higher system level, resulting in reduction of vascular tension
and, thereby, increases in the oxygen ow to active tissues.
The effect of DXXK on muscles relates directly to DXXK’s
TCM symptom treatment pattern, namely muscle cramps
in the neck, lower back, and legs as well as dysfunction of
cardiac muscle. Moreover, this association is consistent with
known manifestations of stress in the musculature, such as
lower back pain (33) and heart attacks (34). The physical
manifestations of chronic stress highlight an important aspect
of integrating physiological and psychological determinants
in both the diagnosis and intervention, a key perspective in
psychoneuroendocrinology (35–37).
Future perspectives
Looking to the future, further studies are needed to obtain a
more detailed accounting of system level actions, particularly
with respect to the dynamics of higher organization systems
and elucidation of biochemical variations among different
clinical subgroups. Furthermore, enhancing our knowledge
of biological rhythmicity and dynamics will be important for
attaining a fuller understanding of systems biology in medicine
(38, 39). Indeed, the notion of dynamic system rhythms being
reected in the manifestation of symptoms over time is key in
TCM. The TCM view of dynamics resonates with the classical
idea of Panta rhei, or “everything ows,” credited to the Greek
philosopher Heraclitus. Major knowledge gaps remain in
our understanding of how psychological and environmental
factors inuence health and in our discernment of higher
system-level organization (40). A systems pharmacology
approach that connects TCM symptom descriptions with
biochemical pathway knowledge has the potential to bridge
these gaps.
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1. I. Prigogine, G. Nicolis, Ann. N.Y. Acad. Sci. 231, 99 (1974).
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(2005).
4. J. van der Greef et al., Planta Med. 76, 2036 (2010).
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8. S. Du, W. Liu, T. Fu, B. Li, Z. Xia, Acta Medica Sinica 37, 267
(2002).
9. X. G. Liang, Q. X. Pang, Chin. J. Geriatr. Heart Brain Vessel Dis. 6,
129 (2004).
10. L. Ni, P. Xu, X. S. Wu, F. Chen, Shanghai Journal of Traditional
Chinese Medicine 41 (11), 76 (2007).
11. K. Ning, Y. Li, H. Cao, L. Li, Trad. Chin. Drug Res. Clin. Pharm. 19,
1 (2008).
12. T. Wang et al., J. Ethnopharmacol. 139, 214 (2012).
13. J. S. Jaswal et al., Biochim. Biophys. Acta 1813, 1333 (2011).
14. C. Cardillo, J. A. Panza., Vasc. Med. 3, 138 (1998).
15. M. Cattaruzza, T. J. Guzik,W. Słodowski,Circ. Res. 95, 841 (2004).
16. K. L. G. Dias et al., Eur. J. Pharm. 574, 172 (2007).
17. G. Gong, Chem. Biol. Interact. 184, 366 (2010).
18. Y. Liu, Y. Lin, Fujian Medical J. 19, 65 (1997).
19. Z. Feng et al., New Drugs Clin. Rem. 13, 152 (1994).
20. S. Xie, J. Zhang, New Drugs Clin. Rem. 13, 161 (1994).
21. Y. P. Zhu, B. G. Li, in Diao Xin Xue Kang Jiao Nang (Science Press,
Beijing, 2004), p. 172.
22. A. L. S. Au et al., Eur. J. Pharm. 502,123–133 (2004).
23. M. Esfandiarei et al., J. Pharm. Exp. Therapeutics 336, 925 (2011).
24. L. Wang et al., Int. J. Clin. Exp. Pathol. 8, 4830 (2015)
25. Y. Y. Guan et al., Acta Pharmacol. Sin. 15, 392 (1994).
26. H. B. Arcasoy et al., Boll. Chim. Farm. 137, 473 (1998).
27. C. Y. Kwan, Acta Pharmacol. Sin. 21, 1101 (2000).
28. Y. H. Wang et al., J. Natural Products (India) 2, 123 (2009).
29. Chinese Pharmacopoeia Commission, Pharmacopoeia
of the People’s Republic of China 2010,
ISBN 9780119207798 (2010).
30. P. Leino-Arjas, S. Solovieva, J. Kirjonen, A. Reunanen, H. Riihimaki,
Scand. J. Work Environ. Health 32, 12 (2006).
31. P. Sterling, Physiol. Behav. 106, 5 (2011).
32. Z. Zhou, New Drugs Clin. Rem. 13, 84 (1994)
33. L. A. Päivi et al., J. Epidemiol. Community Health 43, 293 (1989).
34. E. Mostofsky et al., Heart J. 35, 1404 (2014).
35. P. D. Gluckman et al., Lancet 373, 1654 (2009).
36. B. S. McEwen, Proc. Natl. Acad. Sci. U.S.A. 2012, 1 (2012).
37. B. L. Fredrickson et al., Proc. Natl. Acad. Sci. U.S.A. 110, 13684
(2013).
38. L. Glass, Nature 410, 277 (2001).
39. J. Bass, J. S. Takahashi, Science 330, 1349 (2010).
40. J. van der Greef, Nature 480, S87 (2011).
Acknowledgments
The authors thank Charlotte Lokin for producing the artwork in
Figure 1.
Hypothesis-driven screening
of Chinese herbs for
compounds that promote
neuroprotection
Protection against the loss of
neurons or the retardation of disease
progression is the major challenge for
the treatment of neurodegenerative dis-
orders like Alzheimer’s disease (AD) and
Parkinson’s disease (PD). Current established drug therapies
treat mainly symptoms, leading to cognitive enhancement in
AD or improved movement in PD. However, neuronal repair
or prevention of further degeneration has not been convinc-
ingly demonstrated in humans (1). Common mechanisms of
neuronal damage include, among others: oxidative stress,
mitochondrial dysfunction, autophagy dysfunction, excito-
toxicit y, protein aggregation, and genetic defects (1–3). Prac-
tically all drugs for AD that were neuroprotective in both in
vitro and in vivo preclinical models failed in large clinical tri-
als. Due to this failure, the therapeutic potential of traditional
Chinese medicine (TCM) has recently received increased
attention. Multiple herbs have been tested in cell cultures
or animal models. However, in a situation similar to that of
synthetic drugs, the evidence of neuroprotection in clinical
studies is still unsatisfactory, most likely due to the fact that
the paradigm of treatment with a single chemical entity is not
easily applicable to the complexity of TCM prescriptions (4).
The screening modality bottleneck
In recent decades the search for novel plant-derived
drugs has relied on hypothesis-free, high-throughput
screening (HTS) using metabolomic, proteomic, and
genomic methodologies (5). The professed goal has been
to identify isolated single-target small molecular chemicals
based on compound libraries. However, even the largest
plant compound libraries represent only a small frac tion
of possible chemical diversity of natural products (6).
Further, in vitro HTS hits often lack efcacy in vivo (7). One
instructive example is Huperzine A, an alkaloid isolated from
Huperzia serrata, which showed multiple benecial effec ts in
preclinical models, but failed in a phase 2 clinical study for
AD (8). Research that primarily focuses on monocompounds
isolated from plants carries a high risk that the observed
effects will not be transferable from in vitro or animal models
to clinical practice.
Neurodegeneration is a complex process involving mul-
tiple pathophysiological mechanisms; therefore it seems only
rational to apply a multitargeted approach to a multifac torial
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
FIGURE 2. Conceptual depiction of the preventive effect of Diao Xin Xue Kang (DXXK) on the progression from a healthy to a diseased
condition over time. The graph on the left illustrates a loss of resilience and the allostatic response. The graph on the right illustrates
how intervention with DXXK can bring the system back to a healthy, resilient state, reducing the long-term inuence of stressors.
Authors:
Thomas Friedemann1,
Min Li2†,
Jian Fei3†,
Udo Schumacher4,
Juxian Song2,
Sven Schröder1*
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disease. Accordingly, multicomponent medicines may prove
to be more potent by virtue of multiple bioac tive compo-
nents (9).
TCM herbal mixtures have long been used to treat AD and
PD. Examples include modied Huanglian-Jiedu-Tang (10)
and Fu-Zhi-San (11) for AD and Jia-Wei-Liu-Jun-Zi-Tang (12) or
San-Huang-Xie-Xin-Tang (13) for PD.
Even if controlled clinical trials show
efcacy, elucidating the mechanisms of
action is an onerous challenge due to
the complex chemical composition of
herbal extracts.
Hypothesis-driven screening
The philosophy and practice of
physiology and pathology vary sig-
nicantly between TCM and Western
medicine in that similar pathophysi-
ological features are often described
using dif ferent terminologies. There-
fore, the application of traditional
clinical knowledge to the Western
system requires an interdisciplinary
and intercultural validation process to
identify effective herbal candidates
and develop the optimal experimental
design.
Cell and animal models used to
validate drug candidates from classical
screening processes can mimic
human pathophysiology to a limited
extent. By contrast, the candidate
herbs from a bedside-to-bench-to-
bedside approach have already been
tested successfully in humans. This
latter, hypothesis-driven approach (as
opposed to the hit-and-miss high-
throughput approach) reduces the risk
of running into cost-intensive dead
ends due to inefcacy or unexpected
side effects discovered during clinical
trials. The process begins when
candidate herbs are systematically
reviewed in the scientic and medical
literature for their in vitro, in vivo, and
clinical actions, and discussed by an
interdisciplinary panel of experts. A
substantiated working hypothesis is
then established by analyzing and
integrating the traditional medicinal
usage and current scientic data of
individual herbs and their known bioactive compounds.
Based on this knowledge, one can carefully select in vivo and
in vitro models for the primar y screening and efcacy assay
steps. After initial screening, transcriptomic, proteomic,
and metabolomic analysis can be performed to further
substantiate mode-of-action hypotheses (14).
1HanseMerkur Center for Traditional Chinese Medicine
at the University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
2Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease
Research, School of Chinese Medicine, Hong Kong
Baptist University, Hong Kong, China
3School of Life Sciences and Technology, Tongji
University, Shanghai, and Shanghai Research Center for
Model Organisms, Shanghai, China
4Institute of Anatomy and Experimental Morphology,
University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
†Contributed equally to this work.
*Corresponding Author: schroeder@tcm-am-uke.de
These hypothesis-based screenings should be followed
by mechanistic studies to identify the mode of action of the
drug as a prerequisite for the preparation of clinical trials.
Figure 1 represents a hypothesis-driven screening process
for the evidence-based evaluation of a TCM product. The aim
is not to nd just one single compound for a single pathway,
but rather to apply the procedure to combinations of herbs
or substances, thus enabling the discover y of additive and
synergistic effects, reecting the current practice of TCM.
Substantial optimization of this process is still required,
but it provides a potentially valuable alternative to current,
suboptimal classical screening methods.
Test case: Finding herbs for PD
Following careful consideration, the traditional formula
Jia-Wei-Liu-Jun-Zi-Tang was chosen to test our hypothesis-
based screening methodology. It has previously been shown
to improve symptomatology and communication ability in PD
patient s (12). We screened a series of extracts and com-
pounds from this formula and identied several autophagy
enhancers with neuroprotective effects (15–17). Two repre-
sentative compounds isolated from Uncaria rhynchophylla
(Miq.) Jacks (Gouteng), corynoxine (Cory) and corynoxine
B (Cory B), were found to promote the degradation of
a-synuclein (the main component of Lewy body brils) and
protect dopaminergic neurons by enhancing autophagy in
cell culture and Drosophila models of PD. Cory enhances
autophagy by inhibiting the mechanistic target of rapamy-
cin (mTOR) pathway, while Cory B elicits that same effec t
by targeting HMGB1-Beclin 1 interaction (18) and restores
autophagy inhibited by a-synuclein (15). These two active
compounds may exert synergistic effects, accounting for the
neuroprotective activity. Proteomic /metabolomic analysis
and animal studies are ongoing to clarify the molecular
mechanisms of action and potential preclinical efcacy.
In a second s tudy, hypothesis-driven screening guided
us to Coptis chinensis Franch. (CC) and coptisine (Cop, a
component of CC), both of which showed neuroprotective
effects against oxidative stress-induced cytotoxicity (19).
However, a crude ex tract of CC was more effec tive than
Cop alone (20). Subsequently, we extended our research
to in vitro and in vivo models for PD, using 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse
experiments to create a subchronic PD model, and its
active metabolite 1-methyl-4-phenylpyridinium (MPP+) in
cell experiments. Furthermore, we found that CC and Cop
protected cells from MPP+-induced c ytotoxicity and CC also
protected MPTP-treated mice from movement disorders
and loss of dopaminergic cells in the substantia nigra. Our
data suggested that the neuroprotective effect of CC or
Cop might at least in part be caused by transcriptional
regulation (18). Microarray analyses of the transcriptome of
CC-treated cells revealed only two differentially regulated
genes, MTND1 and TXNIP, which could possibly explain the
neuroprotective ef fect (19, 20).
It is apparent from our work that combining single
compounds or herbs, which ac t via different modes, has
the potential to generate additive or synergistic effects.
Comparing the efcacy of the crude herb, its active
compounds, and traditional mixtures using the herb as an
ingredient, may help us to better understand the scientic
principles behind herbal compositions. Validation of this
promising approach will not be an easy path, and can only
be achieved through the concerned effor ts of a collaborative
network of scientists and medical professionals.
Conclusions
TCM herbal mixtures have been used successfully for mil-
lennia, but their mode of action remains poorly understood.
Nevertheless, they may have an enormous potential due to
their multitarget mode of action for treating multifactorial
complex diseases, including AD and PD, for which satisfactory
conventional treatments do not exist. The classical screening
approach using shotgun methods has not been as successful
as hoped, despite considerable cost and effort. The develop-
ment of hypothesis-driven screening methods is therefore
essential and should result in valuable outcomes.
References
1. C. Holscher, Neural Regen. Res. 9, 1870 (2014).
2. J. L. Cummings et al., Alzheimers Res. Ther. 6, 37 (2014).
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5. A. L. Harvey et al., Nat. Rev. Drug Discov. 14, 111 (2015).
6. D. H. Drewry et al., Curr. Opin. Chem. Biol. 14, 289 (2010).
7. J. L. Medina-Franco et al., Drug Discov. Today 18, 9 (2013).
8. M. S. Rai et al., Neurology 76, 1389 (2011).
9. B. M. Schmidt et al., Nat. Chem. Biol. 3, 360 (2007).
10. S. S. Durairajan et al., PLOS ONE 9, e92954 (2014).
11. M. Bi et al., Neurosci. Lett. 501, 35 (2011).
12. W. F. Kum et al., Evid. Based Complement. Alternat. Med. 2011,
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Med. 2012, 501032 (2012).
14. X. Wang et al., Mol. Cell. Proteomics 12, 1226 (2013).
15. J. X. Song et al., Autophagy 10, 144 (2014).
16. J. H. Lu et al., Autophagy 8, 98 (2012).
17. L. L. Chen et al., J. Neuroimmune Pharmacol. 9, 380 (2014).
18. D. Tang et al., J. Cell Biol. 190, 881 (2010).
19. T. Friedemann et al., J. Ethnopharmacol. 155, 607 (2014).
20. T. Friedemann et al., Evid. Based Complement. Alternat. Med.
2015, 827308 (2015).
Acknowledgments
The authors would like to acknowledge Prof. Wolfgang
Schwarz for the founding and establishment of a scientic
Sino-German Network on TCM research. Thanks to Sarah
Mirza for the illustration. This work was supported by the
HanseMerkur Insurance Group and the Innovation Foundation
Hamburg (721.230-002), and by grants from the General
Research Fund (HKBU 121009/14), the Innovation and
Technology Fund (ITS/274/12), and the Health and Medical
Research Fund (HMRF 12132091) from the Hong Kong
Government (For M. Li).
FIGURE 1. Workow of hypothesis-driven screening with examples from authors’
research. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CC, Coptis chinensis.
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Mapping ancient remedies: Applying a network
approach to traditional Chinese medicine
Over the thousands of years that traditional med-
icine has been practiced, a wealth of clinical experience and
a large number of herbal formulae have been accumulated to
support the practice of traditional Chinese medicine (TCM).
It is challenging to assess TCM therapies that are mechanisti-
cally unclear, in particular because many ingredients in an
herbal formula may exert their effects on the body through
low afnity binding to multiple different targets. This is at odds
with the current “one target, one drug” approach most often
associated with Western therapies, which is committed to the
pursuit of drugs that bind to a single target with high afnity
and specicity. At the same time that the single target-based,
high-throughput screening assays that are the hallmark of
reductionist research are being questioned due to high failure
rates (1), network pharmacology is evolving as a systematic
paradigm for drug discovery and development (2, 3). Network
pharmacology adopts a network approach to represent and
analyze the complex biological systems underlying diseases
and drug actions. It thus aids in drug discovery, drug design,
and drug development, sharing a holistic perspective that
is characteristic of TCM (2–5). Today, the integration of TCM
and network pharmacology (TCM-NP) provides an innovative
research perspective for proponents of both reductionist and
holistic medicine.
Treating a network as a therapeutic target
TCM-NP highlights a “network target, multicomponent
therapeutics” approach (6). The core principle of a network
target is to construct a biological network that can be used
to decipher complex diseases. The network is then used as
the therapeutic target, to which multicomponent remedies,
such as herbal formulae, are applied (5, 6). Here, a network-
based model incorporating an “effect-on” and “effect-off”
switch can be proposed as a means to understand how herbal
medicine might work. For the model to be “on,” multiple
ingredients (or a single ingredient as a special case) in an
herb or herbal formula should induce additive or synergistic
effects on a set of interacting targets within a given network,
such that the nal outcome reaches a threshold to produce a
measureable pharmacological result by network propagation
and integration in both space (spatial extension) and time
(temporal duration) (Figure 1A). In this way, multiple low-
afnity actions can achieve a signicant effect. By contrast, in
the “off” scenario, herbal ingredients that exert opposite or
antagonistic actions on a target network (Figure 1B), or only
weakly affect decentralized targets in a network (Figure 1C),
may not produce effects that reach the measureable threshold.
This model can help to explain why the actual ef cacy of
herbal ingredients can be greater than the sum of the effects
of individual ingredients (7, 8). For example, a recent study
demonstrated that the classic Liu-Wei-Di-Huang formula can
exert diverse therapeutic actions on metabolic and immune
disorders by regulating a set of networked targets through
different groups of bioactive ingredients (9).
According to the proposed effect-switch model, an optimal
combination of herbal ingredients from herbal formulae can
be considered worth pursuing if it satises the criteria for a
network-based effect switch: turning on desirable effects and
turning off undesirable effects (including side effects and
toxicity).
TCM-NP methodologies
Through the development of computational and
experimental methods, TCM-NP aims to map both disease
genes (including gene products) and herb targets in a
network, and provide information on bioactive compounds,
synergistic combinations, mechanisms of action, and modern
indications for herbal formulae by measuring the network
association (e.g., modularity, connectivity, feedback, and
dynamics) between disease genes and herb targets (Figure
2A). Representing complex biological systems as networks
provides a foundation for the exchange of scientic and
clinical data between modern and traditional forms of
medicine. Now, 'omics technologies, knowledge databases,
and bioinformatics are providing more actionable data and
increasingly sophisticated analysis tools, thus accelerating
the understanding of biological networks, a situation that
will undoubtedly speed TCM-NP progress. For example,
by exploiting the available data pool, a computational
method, drugCIPHER, has been developed to predict an
herbal compound’s target prole by integrating chemical,
target, and network information from current FDA-approved
drugs (10). A sibling method, CIPHER, also performed well
in predicting disease genes (11). In recent years, the use of
systems biology and bioinformatics technologies in TCM has
been growing rapidly, as has the generation of TCM-NP data
and our understanding of multilayer networks. Through this
work, associations have been elucidated between herbs,
compounds, molecules, microbes, phenotypes, and diseases
and/or TCM syndromes, generating fresh insights into
holistic traditional medicine.
Not only does network pharmacology reect the holistic
properties of herbal medicine, but the rich trove of data on
the use of TCM as herbal combinations can assist in rening
the network. Considering that we still have much to learn
regarding biological systems and drug action/interactions,
the eld of network pharmacology can undoubtedly
benet by combining top-down and bottom-up strategies.
Since cer tain herbal formulae have been shown to be
clinically effective, the inclusion of this empirical knowledge
Ministry of Education Key Laboratory of Bioinformatics and Bioinformatics Division,
Tsinghua National Laboratory for Information Science and Technology/Department
of Automation, Tsinghua University, Beijing, China
*Corresponding Author: shaoli@mail.tsinghua.edu.cn
FIGURE 1. An effect-switch model based on
the network target can be used to understand
the actions of herbal ingredients and how
their activity can be modulated.
factor PU.1; CDKN1B, cyclin-dependent kinase inhibitor 1B; CEBPB, cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT)/
enhancer binding protein, beta; CEBPE, CCAAT/enhancer binding protein, epsilon; RARB, retinoic acid receptor, beta; AQP9,
aquaporin 9 (15).
FIGURE 2. (A) Schematic
of traditional Chinese
medicine-network
pharmacology (TCM-
NP) methodology. (B) A
representation of a Cold/
Hot Syndrome molecular
network (12). (C) Part
of the Realgar-Indigo
naturalis components
targeted network.
PML, promyelocytic
leukemia; RARA, retinoic
acid receptor, alpha;
RB, retinoblastoma;
MYC, v-myc avian
myelocytomatosis viral
oncogene homolog;
CDK2, cyclin-dependent
kinase 2; SPI1, a gene
encoding transcription
of multicomponent therapeutics may permit exciting
advancements in network pharmacology.
Application of TCM-NP in traditional medicine
TCM-NP promises to help elucidate the complex molecular
mechanisms underlying the actions of traditional therapies as
well as explore new indications for their use. Herbal formu-
lae are traditionally used to treat so-called TCM syndromes
(Zheng). Most medicinal herbs can be categorized as cold,
cool, warm, or hot, based on their composition and nature.
One of the earliest TCM-NP studies showed that Cold and Hot
Syndromes are closely associated with a number of networked
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
O Node: a biological entity
(e.g., molecule, pathway,
biological process)
-—— Edge: a physical or functional
interaction
Author:
Shao Li*
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Drug discovery in traditional
Chinese medicine: From
herbal fufang to
combinatory drugs
Today, drug discovery is a critical issue
in the pharmaceutical industry. Although
global spending on drug discovery and
development has risen sharply in the last
decade, the approval
rate for new drugs
is declining. This situation is mainly due to
drug failure caused by lack of efcacy and/
or safety. One important reason for this is
that common single-drug therapeutics are
rarely able to fully address the complex nature of most human
diseases (1). Producing combinatory drugs—combinations of
multiple drugs against multiple disease targets—is an appropri-
ate approach to address this issue (2).
Traditional Chinese medicine (TCM), a medical system
based on natural products, has been widely used in East
Asia for thousands of years to provide treatments and cures
for disease. The long history and extensive documentation
of TCM clinical practices have accumulated a considerable
number of fufang (herbal compound prescriptions) that exhibit
in vivo efcacy and safety, and provide a unique resource for
combinatory drug discovery.
TCM: Synergy of multiple ingredients
The documented history of TCM dates back more than four
thousand years to the times of Shennong (Yan Emperor), while
mature TCM theory was established during the Song dynasty
(960–1279 CE). TCM theory is based on a holistic, intercon-
nected view of the world. The patient is considered as a system
in which the normal balance of Yin/Yang has been disrupted.
The rst step in the TCM diagnosis process is to determine
the particular Zheng (pattern or syndrome) aficting the pa-
tient (3). In our studies, we analyzed the molecular networks of
Han Zheng (cold pattern) and Re Zheng (heat pattern) in rheu-
matoid arthritis patients. The results indicated that Han Zheng
is related to the Toll-like receptor signaling pathway, while Re
Zheng impacts the calcium and peroxisome proliferator-acti-
vated receptor signaling pathways (4). Characteristic molecular
signatures for each Zheng were also identied (5).
Based on the particular Zheng and characteristics of the
patient, a suitable fufang was chosen for treatment. Fufang
were formulated based on the TCM principle of Jun-Chen-
Zuo-Shi, with Jun (literally “emperor”) being the principal
ingredient that targets the primary causes and symptoms of
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
neuroendocrine-immune molecules, indicating a metabolism-
immune imbalance. Meanwhile certain so-called cold herbs
can target hub nodes in the Hot Syndrome molecular network,
and vice versa, to restore the corresponding network balance
(12) (Figure 2B). It was further found that active compounds
in a cold herbal formula, Qing-Luo-Yin, could synergistically
suppress the cytokine and vascular endothelial growth factor
pathways in a hot network to treat disorders involving inam-
mation and angiogenesis (13).
Moreover, TCM-NP may provide a network-based interpreta-
tion for the Jun-Chen-Zuo-Shi (emperor-minister-assistant-cou-
rier) theory of combining herbal formulae. A disease molecular
network could accordingly be divided into Jun-Chen-Zuo-Shi
target modules to aid in the determination of the optimal
combination therapy (14). For instance, in a Realgar-Indigo
naturalis formula, tetraarsenic tetrasulde as a Jun can target
the promyelocytic leukemia (PML)-retinoic acid receptor alpha
(RARA), a fusion protein involved in acute PML. Indirubin and
tanshinone IIA can act as Chen and Zuo, respectively, by target-
ing the network immediately adjacent to, and interacting with,
PML-RARA, while the Shi targets the membrane channel trans-
porter, aquaporin-9, to aid arsenic transportation (15) (Figure
2C; the target interactions are extracted by using the Search
Tool for the Retrieval of Interacting Genes/Proteins, http://
string-db.org/). Additional TCM-NP case studies have recently
been published (16).
Clearly, the merging of TCM and network pharmacology
is in its early stages. A more in-depth analysis of TCM-NP will
require more powerful computational or experimental method-
ologies and technologies, together with more comprehensive
TCM data. Although the task is challenging, there is much
optimism for the future, particularly with the arrival of the big
data and precision medicine era. Moving forward, TCM-NP
promises to be an innovative way to explore the application
and efcacy of TCM, and can contribute to narrowing the gap
between Eastern and Western medical practices.
References
1. E. C. Butcher, Nat. Rev. Drug Discov. 4, 461 (2005).
2. A. L. Hopkins, Nature Chem. Biol. 4, 682 (2008).
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(2011).
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9. X. Liang et al., Mol. BioSyst. 10, 1014 (2014).
10. S. Zhao, S. Li, PLOS ONE 5, e11764 (2010).
11. X. Wu et al., Mol. Syst. Biol. 4, 189 (2008).
12. S. Li et al., IET Syst. Biol. 1, 51 (2007).
13. B. Zhang et al., Evid. Based Complement. Alternat. Med. 2013,
456747 (2013).
14. S. Li et al., BMC Bioinformatics 11(Suppl. 11), S6 (2010).
15. L. Wang et al., Proc. Natl. Acad. Sci. U.S.A. 105, 4826 (2008).
16. S. Li, T. P. Fan, W. Jia, A. Lu, W. Zhang, Evid. Based Complement.
Alternat. Med. 2014, 138460 (2014).
Acknowledgments
The author thanks Dr. Tai-Ping Fan and his colleagues for their
review of this work and their valuable comments and sugges-
tions. This work is supported by the National Natural Science
Foundation of China (81225025 and 91229201).
the disease, Chen (“minister”) targeting the underlying causes
of the disease and potential protective mechanisms, Zuo (“as-
sistant”) helping the Jun and Chen ingredients to achieve their
optimal curative effects by counteracting any potential adverse
side effects and by treating any secondary symptoms of the
disease, and nally, Shi (“courier”) ensuring that all ingredients
are properly absorbed and delivered to the target organs.
We will use a well-known and clinically tested fufang for
leukemia therapy as an example to illustrate this principle.
The formula, known as Realgar–Indigo formula (RIF), contains
realgar, indigo minerals, and red sage root. Molecular analyses
showed that arsenic in realgar works as Jun by directly attack-
ing the receptor oncoprotein in leukemia cells. Tanshinone,
the active ingredient in red sage root, acts as Chen by partially
restoring those pathways that stop leukemia spreading. Indiru-
bin, the active ingredient in indigo, works as Zuo by antagoniz-
ing the toxicity of arsenic and slowing the growth of leukemia
cells. Lastly, indirubin and tanshinone work as Shi, as these
ingredients can enhance the cellular uptake of arsenic by
increasing the gene expression and synthesis of carrier pore
proteins in the cell membrane (6). Such multiple synergetic
ingredients in fufang offer a unique opportunity to attack mul-
tiple disease-causing mechanisms simultaneously, and make it
a unique resource for the discovery of new combinatory drugs.
Arsenic, the Jun ingredient mentioned above, is now the
primary drug in a combination therapy for acute promyelocytic
leukemia (7). Generally, understanding the pharmacology net-
work of fufang will be useful in TCM-based combinatory drug
discovery. The recent development of 'omics technologies
and in silico methods for analyzing signaling pathways provide
useful tools for understanding the pharmacology network of
various fufang.
The application of 'omics and in silico technologies
'Omics technologies such as genomics, transcriptomics,
proteomics, and metabonomics are high-throughput technolo-
gies used to analyze a variety of molecules simultaneously.
These technologies have facilitated the study of the molecular
pharmacology of fufang at multiple levels (8). However, the
high cost of such studies has thus far limited the number of
fufang studies using 'omics technologies. As a lower cost alter-
native, in silico methods using computational algorithms and
cheminformatics can virtual screen large numbers of drug-tar-
get interactions in order to construct pharmacology networks
of fufang activity (9). In one example, the active compounds
and mechanisms of actions of Gegen-Qin-Lian-Tang for the
treatment of type 2 diabetes were determined by an in silico
approach (10).
A network-based evaluation approach
A primary advantage of fufang is the abilit y to
simultaneously target multiple points within the complex
network of a disease. We established an evaluation approach
to examine the interaction between a fufang and a human
disease network to facilitate the translation of a fufang into a
combinatory drug (Figure 1).
This approach evaluated three effects of the drug: the
major therapeutic effect (MTE), the associated therapeutic
effect (ATE), and any ancillary effects (AEs). MTE is the ability
of the drug to target the af fected disease network and re-
cover normal function, similar to the role of Jun ingredients.
ATE is the drug’s ability to enhance the effec ts of the MTE
and provide protection against negative side effects, as pro-
vided by Chen and Zuo. AEs refer to any additional assistive
mechanisms, similar to the role of Shi ingredients.
Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of
Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
†Contributed equally to this work.
*Corresponding Authors: zhangge@hkbu.edu.hk (G.Z.) and aipinglu@hkbu.edu.hk (A.L.)
FIGURE 1. Overview: From herbal fufang to combinatory drugs.
Authors:
Bing He†,
Cheng Lu†,
Maolin Wang,
Guang Zheng,
Gao Chen,
Miao Jiang,
Xiaojuan He,
Zhaoxiang Bian,
Ge Zhang*,
Aiping Lu*
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The evaluation of ingredients considers three aspects: cov-
erage of the fufang target network, the ability of the formula
to alter the target’s function, and the impact of this alteration
on the disease network. Here, we provide an example to il-
lustrate the general evaluation process and its contribution to
combinatory drug discovery. Bizheng-Tang, the decoction of
eight ingredients, could help overcome the low response of
leunomide in rheumatoid arthritis (RA) treatment. To simplify
Bizheng-Tang, we studied the gene expression proles of
low-response RA mice before and after Bizheng-Tang adminis-
tration, as well as the effect of each separate ingredient in the
formula. The results suggested that Rhizoma Ligustici Chuanx-
iong plays an essential role in Bizheng-Tang. Further clinical
trials conrmed that ligustrazine, the active component of Rhi-
zoma Ligustici Chuanxiong, in combination with leunomide
effectively overcame the low response to RA treatment (11).
This simplied approach for evaluation of fufang ingredi-
ents demonstrates a potential way to discover combinatory
drugs, although further testing and verication of this process
is still required.
Future work
To date, only a small number of fufang have been studied
using advanced 'omics technologies and in silico methods.
Although 'omics technologies are powerful, results are sus-
ceptible to variability caused by the use of nonstandardized
research materials. Proper standards must therefore be estab-
lished to better control study-to-study variation. In silico meth-
ods used for virtual screening have been developed mainly
for Western chemical medicine and a one-drug, one-target
system. They are often not sufciently powerful to handle the
complex multidrug, multitarget nature of fufang. New algo-
rithms therefore need to be developed specically for fufang.
When trying to develop combinatory drugs from fufang, one
of the most challenging steps is deciding on a short list of ef-
fective formulae from the extensive ancient and contemporary
literature, as there are over 11,000 plant species used in more
than 100,000 fufang in China. The future discovery of combi-
natory drugs from fufang will benet from the development
of a research platform that contains biological information on
fufang herbs and compounds, and on data from standardized
'omics studies, all integrated using TCM-specic in silico tools.
References
1. J. W. Scannell, A. Blanckley, H. Boldon, B. Warrington, Nature
Rev. Drug Dis. 11, 191 (2012).
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3. M. Jiang et al., J. Ethnopharmacol. 140, 634 (2012).
4. C. Lu et al., Rheumatol. Int. 32, 61 (2012).
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pdf/Abstract-Book(2014).pdf.
The polypharmacokinetics
of herbal medicines
The pharmacokinetics (PK) of multicom-
ponent herbal medicines (HMs) is a long-
standing bottleneck for botanical drug and
traditional medicine research. There are a number of reasons
for this. One is the sheer number of plant-derived molecules
that are typically present in HMs, which presents a substantial
challenge to chemical and pharmacological evaluation. This
is further complicated by the wide concentration range of the
components. Another factor is the dynamic nature of chemi-
cal interactions between the plant-derived molecules and
endogenous molecules. These interactions shape the PK of an
HM and, consequently, the treatment outcome for individual
patients. Monitoring the chemical components is made still
more challenging by a lack of authenticated standards, by the
complexity of both botanicals and biological sample matri-
ces, and by the need for cross-disciplinary expertise involving
'omics sciences, biochemistry, pharmacology, bioinformatics,
and systems modeling. As a result, current research on the
PK of HMs is still in its infancy. It is largely focused on in vivo
characterization of one or two key HM components, the results
of which may be difcult to link to the holistic treatment effects
that result from drug-drug interactions (1).
A Poly-PK Approach
The traditional approach to understanding the pharmacol-
ogy of a multicomponent agent is to study the effects of single
active components on well-dened targets, such as specic
enzymes or genes. However, it has proven impractical to inte-
grate the results obtained using these reductive approaches
to generate a systems understanding of concerted pharmaco-
logical interventions (2). The attempts to characterize the PK of
multicomponent natural products have, however, demonstrat-
ed that the PK behavior of a given phytochemical is altered by
coexisting constituents (3–5).
The advent of comprehensive proling technologies offers
tremendous new opportunities for understanding multicom-
ponent PK. Phytochemical proling and metabolomics can be
coupled to multivariate statistical tools to generate multipa-
rametric assessments. These allow us to create a concentra-
tion–time prole of a multicomponent HM, which we call a
“Poly-PK,” as well as other health determinants associated with
the intervention.
We recently proposed an integrated proling approach. It
uses tandem mass spectrometry (MS) to provide quantitative
dynamic concentration proles of bioavailable xenobiotic
molecules that result from in vivo absorption, and hepatic and
gut bacterial metabolism, of herbal agents (6, 7). This Poly-PK
approach takes into account both the diversity of the HM’s
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
chemical composition and its complex effects on the metabolic
pathways of the mammalian system. When HMs enter our
body, there are signicant metabolite prole changes over
time, which fall into three categories as illustrated in Figure 1:
(1) HM-derived compounds absorbed into the circulation, (2)
new metabolites generated by the chemical transformation of
HM compounds by hepatic enzymes and gut microbes, and
(3) endogenous metabolites that are altered in response to the
HM intervention.
Certain essential PK variables, such as maximum plasma
concentration (Cmax) and the time to reach Cmax (tmax), can be
1Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine,
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated
Sixth People’s Hospital, Shanghai, China
2University of Hawaii Cancer Center, Honolulu, Hawaii
3E-institute of Shanghai Municipal Education Committee, Shanghai University of
Traditional Chinese Medicine, Shanghai, China
4Angiogenesis and Traditional Chinese Medicine Laboratory, Department of
Pharmacology, University of Cambridge, Cambridge, United Kingdom
*Corresponding Author: wjia@cc.hawaii.edu
obtained directly from the measured
concentration data, while parameters
such as the area under the concentra-
tion–time curve and the elimination
half-life (t1/2) can be generated using PK
modeling software.
Poly-PK in Action
We recently provided proof-of-
concept for the above strategy (8). The
study characterized the in vivo absorp-
tion and metabolism in humans of the
phytochemicals of Pu-erh, a fermented
tea produced in Southwest China. Pu-erh,
which contains a large array of polyphe-
nolic constituents, has a range of phar-
macological properties, including the
ability to reduce blood levels of triacylg-
lycerol and total cholesterol (9, 10). Urine
samples were collected from volunteers
at 0, 1, 3, 6, 9, 12, and 24 hours follow-
ing consumption of tea, and once a day
during a six-week period that included
a two-week baseline phase, a two-week
daily Pu-erh tea ingestion phase, and a
two-week “wash-out” phase. Volunteers
were provided with standard meals for
six weeks.
The Pu-erh tea water extraction and
urine samples collected at the differ-
ent time points were analyzed using
ultraperformance liquid chromatog-
raphy-quadrupole time-of-ight (TOF)
MS and gas chromatography-TOF MS.
This analysis generated 1,075 detected
features from Pu-erh tea and 6,028 from
urine samples (n = 12). The urinary me-
tabolome dataset was subjected to uni-
variate s tatistical analysis, yielding 2,652
variables that were altered by Pu-erh tea
intake (P < 0.05). Using multivariate simi-
larity analysis to compare the altered
variables to the Pu-erh tea metabolome
or the predose urine metabolome, we
identied 19 absorbed tea polyphenols, 26 metabolites of
the absorbed polyphenols, and 118 endogenous metabolites
altered due to tea intake. Subsequent analysis demonstrated,
for the rst time, a correlation among the dynamic concentra-
tion proles of bioavailable tea components and the human
metabolic response prole (Figure 2). This type of approach,
in which scientists simultaneously monitor the PK behaviors
of multiple phytochemicals in vivo, will lead to the direct elu-
cidation of the pharmacological and molecular mechanisms
underlying HMs (8).
Perspectives
Over the past two decades HMs have been used increas-
ingly as therapeutic interventions against a number of
conditions (2, 11, 12). The pharmacology of HMs involves a
“network” in which multiple components interact with multiple
targets in vivo to exert a holistic treatment effect. The Poly-PK
strategy described here uses an integrated phytochemical
FIGURE 1. A Poly-PK strategy. The pharmacokinetic (PK) study of multicomponent
herbal medicines (HMs) that integrates phytochemical and metabolite proling.
Authors:
Wei Jia1,2,3*,
Tai-ping Fan4,
Xiaoning Wang3,
Guoxiang Xie2
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Traditional Chinese medicine (TCM)
focuses on disease prevention and
treatment using personalized therapies.
The bioavailability barrier (BB) deter-
mines the concentration of drug being
taken up by the human body, controlled
by efux transporters (ETs) and drug-
metabolizing enzymes (DMEs), which are primarily regulated
by nuclear receptors (NRs). Hence, polymorphisms of DMEs,
ETs, and NRs can affect the pharmacokinetics of drugs, which
ultimately inuences the efcacy and/or toxicity of Chinese
herbal formulas (CHFs). This paper presents the reconstruc-
tion of a BB-based network with new insights that help eluci-
date the therapeutic mechanisms of CHFs.
Western medicine focuses on molecular target-based ther-
apy; however, there are limitations in transforming genotype-
based or disease-oriented medicine into personalized and net-
work-based clinical therapy (1). In contrast to Western medicine,
CHFs achieve their effect through personalized modulation of
a patient’s health status. However, CHFs have not been widely
accepted because their treatment mechanism has not yet been
well dened (2). Determining how the components of CHFs will
behave in the body is a pivotal aspect in determining treatment
mechanisms of TCM. The BB has a key function in controlling
absorption, biotransformation, and clearance of drugs in vivo
(3). Therefore, a BB-based approach together with biological,
biochemical, 'omics, and computational technologies is a pow-
erful driver for establishing today’s personalized TCM model.
The composition and characteristics of the
BB network
The BB can be dened as a physiological defense net-
work, because it plays a central role in preventing xenobiotic
interference in the human body (3). The network is composed
mainly of ETs and DMEs that are distributed in the liver and
intestine, responsible for drug distribution and elimination
(Figure 1A). ETs and DMEs are regulated by nuclear recep-
tors (NRs) that respond to the endogenous and/or exogenous
ligands (4). DMEs include cytochrome P450 and conjugating
enzymes such as uridine 5’-diphospho-glucuronosyltransfer-
ases (UGTs) and sulfotransferases (SULTs). ETs refer to the trans-
membrane adenosine triphosphate (ATP)-binding cassette
and metabolomic proling strategy coupled with multivariate
statistical analysis to simultaneously monitor multiple HM com-
ponents for pharmacological evaluation. This approach reveals
the interrelationships between xenobiotics and endobiotics
as well as the metabolic impact [using pharmacodynamic (PD)
endpoints] of HM agents, providing an unprecedented level of
insight into the mechanisms of action for HMs.
Most HMs are administered orally and are therefore
exposed to microorganisms in the gut. The symbiotic gut
microbiota performs a wide variety of biochemical transfor-
mations in which phytochemical compounds are selectively
metabolized into active or absorbable components by
microbial enzymes. Thus, two sets of genomes—our genome
and gut microbiome—comodulate the absorption, distribu-
tion, metabolism, and excretion of HM compounds, generat-
ing a patient-specic PK prole. Many HM ingredients that
were believed to be nonabsorbable and nonactive, such as
polysaccharides and lignans, may have signicant activities
in vivo af ter oral administration, highlighting the important
role that the human gut microbiota plays in HM pharmacolo-
gy (13–15 ). A Poly-PK strategy can facilitate the development
of personalized pharmacological evaluation of HMs, linking
different patient responses to HM interventions. PK is often
studied in conjunction with PD, and the Poly-PK strategy pro-
posed here can simultaneously monitor PD markers through
the measurement of multiparametric metabolic changes and
other pharmacological endpoints (6). To achieve the desired
HM therapeutic effect, each of the multiple components of
the remedy will require a complete and dynamic panel of
PK parameters. This information is essential for minimizing a
drug’s toxicity, reducing the chances of overdosing a patient
or inducing drug complications, and, ultimately, improving
patient compliance—and the quality of patients’ lives.
We each possess a unique metabolic phenotype, known
The bioavailability
barrier and personalized
traditional Chinese
medicine
as a metabotype, that is characterized by endogenous
metabolites and a panel of exogenous metabolites
acquired from food consumption and/or drug treatments.
This metabotype affects our individual metabolism of,
and response to, any given HM. The Poly-PK strategy can
unravel the complex interac tions between the multiple
components in HMs and in mammalian metabolic systems.
The advent of the Poly-PK technology will greatly accelerate
the holistic pharmacological evaluation of HM candidates
and advance novel therapeutic developments. Furthermore,
understanding the metabolic fate of a multicomponent drug
is also a critical step toward developing the next generation
of combinatorial chemical drugs, which will maximize the
synergistic effects of cer tain drug components and help to
prevent their undesirable metabolic side ef fects.
References
1. K. Ito et al., Pharmacol. Rev. 50, 387 (1998).
2. T. Xue, R. Roy, Science 300, 740 (2003).
3. C. Xiang et al., Drug. Metab. Dispos. 39, 1597 (2011).
4. X. Qiao et al., J. Chromatogr. A 1258, 84 (2012).
5. S. M. He, E. Chan, S. F. Zhou, Curr. Pharm. Des. 17, 357 (2011).
6. K. Lan, W. Jia, Curr. Drug. Metab. 11, 105 (2010).
7. K. Lan, G. Xie, W. Jia, Evid. Based Complement. Alternat. Med.
2013, 819147 (2013).
8. G. Xie et al., J. Proteome Res. 11, 3449 (2012).
9. J. K. Lin, S. Y. Lin-Shiau, Mol. Nutr. Food Res. 50, 211 (2006).
10. K. L. Kuo et al., J. Agric. Food Chem. 53, 480 (2005).
11. R. L. Blaylock, J. Am. Nutraceut. Assoc. 2, 19 (1999).
12. J. M. Hollander, J. I. Mechanick, J. Am. Diet. Assoc. 108, 495
(2008).
13. E. D. Sonnenburg et al., Cell 141, 1241 (2010).
14. X. Xu et al., Biotechnol. Adv. 31, 318 (2013).
15. M. Blaut, T. Clavel, J. Nutr. 137, 751S (2007).
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
FIGURE 2. Poly-PK metabolomic proles. The relationships among the three groups of metabolites associated with Pu-erh tea are
visualized using correlation maps, as shown by red (positive) or blue (negative) lines.
Authors:
Lin-Lin Lu1,
Xiao-Hong Liu1,
Elaine Lai-Han Leung3,
Ying Wang1,2,
Jian Shi1,2,
Ming Hu1,4,
Liang Liu3*,
Zhong-Qiu Liu1,2*
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efux transporters (3). P-glycoprotein (P-gp), multidrug resis-
tance protein 2 (MRP2), and breast cancer resistance protein
(BCRP) on the apical membrane are the most important ETs,
delivering or excreting drug metabolites. MRP1 and MRP3 on
the basolateral membrane regulate the entry of drugs into
the bloodstream. Multiple ETs and DMEs couple to create a
complex network regulating disposition of drugs, particularly
natural polyphenols abundant in CHFs (3).
Drug bioavailability depends not only on the activity of
DMEs, but is also inuenced by ETs (3). Therefore, variations
in levels and activit y of DMEs and ETs can markedly inu-
ence the pattern or pathway coupling in the BB network. For
example, genetic variants of CYP2C19 and CYP2D6 are asso-
ciated with reduced responses to the antiplatelet clopidogrel
and the antiestrogen tamoxifen, respectively. The antibiotic
doxorubicin exhibits individual differences that maximize
therapeutic efcacy and minimize side effects on the basis
of genetic variants of the regulatory pregnane X NR receptor
(PXR), ETs (ABCB1, ABCG2, ABCC5, ABCB5, and RLIP76), and
DMEs (CBR1, CBR3) (5). Therefore, the BB network is a critical
determinant for implementing personalized medicine.
The BB network and harmonizing CHF ecacy
and toxicity
A personalized treatment paradigm is central to the holis-
tic and integrated approach of TCM. CHFs provide a valu-
able way to study the underlying multitarget mechanisms
of personalized TCM treatments. In TCM, the most impor-
tant principle of formulating CHFs is the Jun-Chen-Zuo-Shi
(emperor-minister-assistant-courier) principle, which holds
that each herb has its own diverse func tion (6). The biologi-
cal functions of a CHF are harmonized by BB ltration in the
body to achieve ideal therapeutic efcacy with minimal toxic-
ity (Figure 1B).
BB ltration can optimize absorption and biotransfor-
mation of ac tive and toxic components in CHFs to create
a “reharmonized” formulation. The BB mainly exhibits
this harmonization effect by bidirectionally driving
the bioavailability of ac tive and/or toxic components.
Specically, the bioavailability of active components in CHFs
can be enhanced by inhibiting the functions of DMEs and/
or ETs in the BB, with consequent improvement in positive
1International Institute for Translational Chinese Medicine, Guangzhou University of
Chinese Medicine, Guangzhou, China
2School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of
Science and Technology, Macau (SAR), China
4Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy,
University of Houston, Houston, TX, USA
*Corresponding Authors: lliu@must.edu.mo (L.L) and liuzq@gzucm.edu.cn (Z.L.)
pharmacological effects. In contrast, the BB prevents the
overabsorption of toxic compounds in CHF (Figure 1B).
For example, Scutellaria baicalensis contains abundant
amounts of diverse polyphenols that possess anticancer
and antiaging effects (3). MRP2/BCRP and UGTs/SULTs
block the bioavailability of polyphenols, resulting in a
reduction in pharmacological effects (7). However, ETs can
act as molecular switches that facilitate the bioavailability of
polyphenols (3).
Another example is Radix aconite, an herb considered to
be clinically unsafe. Toxic aconitum alkaloids like aconitine
have low bioavailability because of the resistance produced
by the BB that limits their toxicity (8). In par ticular, CYP3A4,
coupled with P-gp, BCRP, and MRP2 in the BB, blocks the
entry of specic toxins into the blood (9). Thus, the rational
use of such toxic herbs could be controlled by limiting
the nal dosage to a relatively safe level, not beyond the
“resistance” capacity of the BB net work. Notably, NRs
could interact with the active/toxic component s to alter
the func tions of DMEs and ETs, and consequently affect BB
ltration. For example, Radix glycyrrhizae, popularly used as
a Shi herb in CHF, activates PXR (10).
In summary, the BB-based network manipulates disposi-
tion of the active/toxic components in CHF via dual-direc-
tional regulation to achieve the maximal efcacy and minimal
side effects of CHF. As such, the BB-based network is able to
act as an intelligent, adaptive system for self-defense, while
genomic variations of ETs and DMEs result in an individual-
ized BB, which ultimately personalizes TCM treatment by
controlling the transport behaviors of CHF (Figure 2).
Perspectives
The BB net work is a complex system, largely because of
the interplay of its key elements of DMEs, ETs, and NRs. It
differs markedly among different individuals due to their
unique polymorphisms and genotypes (11). The BB can be
treated as a personalized system that induces the same drug
to produce a variety of ac tions
and toxicities in different
individuals. In the future,
characterization of personalized
BB-based networks will bring
a new era in both TCM and
conventional medicine.
The essence of TCM is an
individualized therapeutic
system using CHF (12), which
is consistent with the principles
of personalized BBs. By taking
into account BB ltering, CHF
can be optimized to produce
harmonized, multicomponent,
multitarget formulae to achieve
optimal effectiveness and low
toxicity. We therefore recom-
mend that future CHF research
should be implemented
together with evidence-based,
personalized, and advanced BB
research methodologies. The
precise molecular mechanisms
underlying each personalized
BB need to be elucidated. Applying 'omics-related tech-
nologies such as metabolomics, proteomics, genomics, and
computational prediction to prole individual BB network
differences caused by polymorphisms or BB interaction factors
could help to assess the unique effects of CHFs in different
individuals (Figure 2). In conclusion, the BB network works not
only as an indispensable tool for clarifying the mechanisms
underlying CHF, but can also be used for characterizing and
optimizing personalized TCM therapies.
References
1. E. E. Schadt, Nature 461, 218 (2009).
2. T. P. Fan et al., J. Ethnopharmacol. 140, 568 (2012).
3. M. Hu, Mol. Pharm. 4, 803 (2007).
4. M. Wagner, G. Zollner, M. Trauner, Hepatology 53, 1023 (2011).
5. K. M. Giacomini et al., Sci. Transl. Med. 4, 153ps118 (2012).
6. T. P. Fan et al., Trends Pharmacol. Sci. 27, 297 (2006).
7. E. Wenzel, V. Somoza, Mol. Nutr. Food Res. 49, 472 (2005).
8. L. Ye et al., Toxicol. Lett. 216, 86 (2013).
9. Z. Cai, Y. Wang, L. J. Zhu, Z. Q. Liu, Curr. Drug Metab. 11, 197
(2010).
10. Y. Mu et al., J. Pharmacol. Exp. Ther. 316, 1369 (2006).
11. P. E. Ferreira et al., Ther. Drug Monit. 30, 10 (2008).
12. L. Liu, E. L. Leung, X. Tian, Nature 480, S100 (2011).
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (81120108025) and the Macau Science
and Technology Development Fund (092/2012/A3).
FIGURE 2. Personalized CHF therapy manipulated by the BB network.
FIGURE 1. Composition of the
BB network and its functions. (A)
The molecular composition of the
bioavailability barrier (BB) network in the
liver and intestine. (B) The bidirectional
activity of the BB network during
harmonization, indicated by positive
(left) and negative (right) resistance
to active (yellow circle) and toxic (red
triangle) components of Chinese herbal
formulas (CHFs). P-gp, p-glycoprotein;
BCRP, breast cancer resistance protein;
MRP2, multidrug resistance protein 2;
UGTs, UDP-glucuronosyltransferases;
SULTs, sulfotransferases; ETs, efux
transporters; DMEs, drug-metabolizing
enzymes.
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Doctors practicing TCM use their extensive knowledge
and experience of syndrome differentiation in clinical prac-
tice to diagnose patients before choosing which acupoints
to stimulate. How each acupoint relates to a disease is based
on both TCM meridian theory and many hundreds of years of
empirical knowledge. For example, a transdermal herbal patch
could be applied on acupoint Shen Que (RN8) for treating
diarrhea, menstrual pains, or indigestion; whereas a patch on
acupoint Yong Quan (KI1) treats high blood pressure, neur-
asthenia, or the common cold. Some common diseases and
the corresponding treatment acupoints are summarized in
Table 1 (6–18). All have been carefully selected from published
clinical research papers using controlled trials and at least
100 cases. Liu and colleagues systematically reviewed the use
of an acupoint herbal patch for treating allergic rhinitis and
chronic obstructive pulmonary disease (COPD) in the stable
phase using a meta-analysis. They included 21 randomized
controlled trails (RCTs) involving a total of 2,327 participants
(allergic rhinitis) and 20 RCTs involving 2,438 participants
(COPD). The authors concluded that an herbal patch alone, or
in combination with Western medicine (2011 Global Initiative
for Chronic Obstructive Lung Disease guidelines), appeared to
be effective for treating these diseases (19, 20).
Recent advances in transdermal herbal preparations
Historically, the most common way to apply transdermal
herbal preparations was using a black plaster. To prepare
the plaster, herbs were fried in edible oil and red lead oxide
(Pb3O4) was added to the rened herb oil to form a sticky
mass. In recent years, however, since the advent of medicinal
polymers, use of a black plaster has gradually given way to
adhesive plasters, gel plasters, or patches, which have the sig-
Transdermal treatment with Chinese herbal
medicine (CHM) has a long history of clinical ap-
plication and theory in China. The earliest record of
its use can be found in the ancient classic, Huang Di Nei Jing
(227 BCE). The practice of transdermal treatment continued
to evolve, reaching its highest popularity during the Qing
dynasty, as elaborated in the book Li Yue Pian Wen (Wu Shi-Ji,
1864). It was emphasized in this book that the principles of
treatment for both external and internal application of CHM
were the same (1). This statement was the forerunner of the
theory of transdermal administration for CHM, and modern
transdermal drug delivery systems (TDDS) use the same con-
cepts, although the precise delivery method is different.
The process of applying transdermal herbal medicine is not
as simple as putting it directly on the skin. It should be applied
specically at the relevant acupuncture points (acupoints).
According to Wu Shi-Ji, “If a disease is due to an external fac-
tor, you should apply herbs to release it on location; however,
when the disease has spread into the body, you should apply
herbs on the relevant acupuncture points to treat it.” (1). Thus,
transdermal treatments exert their therapeutic actions not only
by absorption of active ingredients from herbs, but also the
stimulation of acupoints. This concept is one of the distinctive
differences between Chinese transdermal herbal treatments
and modern TDDS (Figure 1).
Acupoints for treatment
The theory of acupoints and meridians is an important part
of traditional Chinese medicine (TCM). The meridian system
(or channel network) is believed in TCM theory to be the path
along which the “qi,” or life energy, flows. According to this
theory, qi and blood ll the meridian system, the channels,
and are transported throughout the body via these meridians,
feeding the organs. Modern biologists have discovered that
there are convergent points of the organs’ qi and blood along
meridians (2). Placing an herbal patch directly on the acupunc-
ture point therefore helps to maximize its therapeutic effects,
with the aggregate effect being a combination of herbal action
plus the acupoint response acting synergistically. The curative
effect of an herbal patch placed on an acupoint is commonly
regarded as superior to that of a patch placed on a non-acu-
point (3). Reports on comparing responses of acupoints with
non-acupoints indicate noticeable differences (4, 5).
1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing,
China
2Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine,
Beijing, China
3Hallam Institute of Chinese Medicine, Sheffield, United Kingdom
*Corresponding Author: qwu@vip.sina.com
Transdermal treatment with Chinese
herbal medicine: Theory and clinical
applications
nicant advantage of reducing skin
irritation. The technologies for extrac-
tion have also improved, allowing
more concentrated extracts of active
herbal ingredients to be made, thus
facilitating percutaneous absorption
of the multiple components of the
herbal formula. Inclusion of carrier
compounds such as microemulsions
(21), liposomes (22), and cyclodextrin
(23) can improve the compatibility of
complex components and polymer
materials. The latest transdermal
herbal preparations can be more
easily prepared, undergo improved
quality control checks, and possess
better stability than in the past (23).
Moreover, pharmaceutical scientists
are experimenting with the use of
aromatic herbs that can act as natural
transdermal uptake enhancers (24),
which will potentially broaden their
clinical application in the future.
References
1. S. Wu, Li Yue Pian Wen, 2nd Ed.
(China Press of Traditional Chinese
Medicine, Beijing, 2007).
2. L. Zheng, Chin. Acupunct.
Moxibustion 4, 222 (2003).
3. Y. Sui, China J. Found. TCM 9, 53
2003).
4. X. Guo, X. Liu, China Journal of Chinese Materia Medica 37,
1035 (2012).
5. L. Xu, Z. Cai, J. TCM External Treat. 14, 6 (2005).
6. Y. Liang, Chin. J. Integr. Tradit. Western Med. 10, 1424 (2013).
7. G. Li, L. Wang, Y. Lin, Chin. J. Integr. Tradit. Western Med. Intens.
Crit. Care 9, 1187 (2011).
8. M. Zhao, F. Qiao, X. Shen, J. Tradit. Chin. Med. 19, 1661 (2012).
9. Y. Liu, J. Shen, R. Wang, J. Tradit. Chin. Med. 10, 620 (1994).
10. L. Sun, S. Lin, S. Tong, Chin. Acupunct. Moxibustion 5, 21 (1995).
11. L. Xu, Y. Zhang, Y. Zheng, Chin. Acupunct. Moxibustion 3, 192
(2010).
12. J. Hu, F. Yang, Lishizhen Med. Materia Medica Res. 6, 1445
(2013).
13. M. Chen, H. Zhang, J. Li, Chin. Acupunct. Moxibustion 9, 725
(2012).
14. S. Wang, D. Lu, Y. Li, Chin. Acupunct. Moxibustion 4, 265 (2009).
15. L. Hang, Z. Cai, Y. Zhu, Chin. Acupunct. Moxibustion 7, 577
(2013).
16. X. Wu, Z. Liu, X. Zhang, Chin. J. Integr. Tradit. Western Med.
Intens. Crit. Care 1, 39 (2004).
17. L. Yin, Y. Li, S. Wang, Chin. Acupunct. Moxibustion 6, 402 (2008).
18. N. Jiao, Chin. J. Exp. Tradit. Med. Formulae 12, 293 (2011).
19. F. Zhou, P. Liu, Integrative Medicine Research 4, 144 (2015).
20. F. Zhou et al., World Journal of Traditional Chinese Medicine 1,
45 (2015).
21. X. Li, Q. Wu, China Materia Medica 38, 37 (2013).
22. Y. Yuan, P. Huang, X. Yang, Chinese Pharmacist 7, 17 (2014).
23. X. Xiong et al., Chinese Journal of Experimental Traditional
Medical Formulae 17, 22 (2011).
24. Y. Lan et al., J. Zhejiang Univ.-Sci. B 15, 153 (2014).
Acknowledgments
Thanks to Dr. Yi Lan, Bochen Zhao, and Wenping Wang for
their contributions to this article.
FIGURE 1. A variety of systemic
diseases can be treated by
application of transdermal
Chinese herbal medicine (CHM)
patches on meridian acupoints.
A combination of acupoint
stimulation and the active
ingredients in the CHM elicit a
healing response.
Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
TABLE 1. Diseases and the corresponding acupoints for treatment (6–18).
*Chronic obstructive pulmonary disease (stable phase). DC, Ding Chuan; DH, Da Heng; DZ, Da Zhui; FS,
Fei Shu; GH, Gao Huang; GS, Ge Shu; GY, Guan Yuan; GYS, Guan Yuan Shu; JBL, Jing Bai Lao; MM, Ming
Men; NG, Nei Guan; PS, Pi Shu; QH, Qi Hai; SD, Shui Dao; SJX, Shang Ju Xu; SQ, Shen Que; SS, Shen Shu;
TS, Tian Shu; XS, Xin Shu; YQ, Yong Quan; ZG, Zi Gong; ZJ, Zhong Ji; ZSL, Zu San Li; ZW, Zhong Wan.
Authors:
Qing Wu1*,
Ling Dong1,
Jianping Liu2,
Dan Jiang3
Disease Acupoints
Asthma in children FS (BL13); XS (BL15); GS (BL17)
CODP (SP)* FS (BL13); XS (BL15); GS (BL17)
Allergic rhinitis DZ (DU14); FS (BL13); PS (BL20); SS (BL23)
Pneumonia in children FS (BL13); GS (BL17); JL (EX-HN15); GH (BL43); Ashi
Respiratory infection
in children FS (BL13); DC (EX-B01); GH (BL43)
Brady arrhythmia NG (PC6); XS (BL15)
Insomnia SQ (RN8); NG (PC6); YQ (KI1)
Dysmenorrhea caused
by endometriosis ZJ (RN3); GY (RN4); ZG (RN19)
Dysmenorrhea ZJ (RN3); GY (RN4); QH (BL24)
Ulcerative colitis SJX (ST37); TS (ST25); ZSL (ST36); MM (DU4); GY (RN4)
Chronic renal failure SQ (RN8)
Simple obesity ZW (RN12); GY (BL26); QH (RN6); TS (ST25); SD (ST28); DH (SP15)
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Insomnia—difculty fall-
ing and staying asleep—is a
frequent complaint, with about
one-third of the general popu-
lation worldwide presenting with symptoms
(1). Although the neural mechanisms underly-
ing chronic insomnia are poorly understood,
substantial evidence has shown that it is a
disorder of physiological hyperarousal involv-
ing both the central nervous system (CNS) and
autonomic nervous sys tem (ANS) (2, 3).
Acupunc ture has been widely used for the
treatment of insomnia in Asia. According to
the theory of traditional Chinese medicine
(TCM), the mind (or shen) is situated in the
heart region; insomnia is considered to be a
disorder of the heart, so acupunc ture points
on the heart and pericardium are often used
in treatment (4). Recently, several systematic
reviews have hinted that acupuncture may be
an effective treatment for insomnia. However,
decits in study design and quality have
meant that denitive conclusions could not be
drawn (5).
Other studies have shown that acupuncture
may be able to increase β-endorphin
production and μ-receptor activity (6), both
of which are associated with enhanced
non-rapid eye movement (NREM) sleep.
Acupunc ture also appears to regulate various
neurotransmitters and hormones involved
in sleep regulation, including β-endorphin,
serotonin, acetylcholine, nitric oxide,
melatonin, dopamine, gamma-aminobutyric
acid (GABA), and neuropeptide Y (NPY)
(7–9). Fur ther reports have suggested that
acupunc ture may be related to a signicant
increase in secretion of melatonin, a hormone
involved in regulation of day-night cycles,
in insomnia patients (10). In both animal and
human clinical studies, evidence indicates
that acupuncture inhibits sympathetic
nervous system ac tivity and regulates the
hypothalamic-pituitary-adrenal (HPA) axis
(11), which may contribute to its mechanism
of counteracting insomnia. This review
summarizes the evidence of the possible
Acupuncture as a potential treatment
for insomnia
ACTH and corticosterone levels. Another study demon-
strated that electroacupunc ture at Zusanli (ST36) prevent s
an increase in stress-induced adrenal NPY messenger RNA
(mRNA) expression (20). The increased adrenal NPY expres-
sion may result from central signals from either CRH or NPY,
which are elevated in the PVN of stressed rats (Figure 1),
suggesting that electroacupuncture inhibits the sympathetic
NPY pathway by activating neurons in the PVN.
Conclusions
Emerging evidence suggests that acupuncture treatment
counteracts insomnia by reducing hyperarousal of the ANS
and through regulation of HPA activation. However, the
mechanisms underlying acupunc ture’s actions in insomnia
are still far from clear. Further research measuring anatomical
location and physiological func tion are warranted to better
understand the mechanisms of acupunc ture in the manage-
ment of insomnia.
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Materials that appear in this section were not reviewed or
assessed by Science Editorial staff, but have been evaluated by
an international editorial team consisting of experts in traditional
medicine research.
1School of Chinese Medicine, the University of Hong Kong, Hong Kong, China
2Department of Psychiatry, the University of Hong Kong, Hong Kong, China
3Susan Samueli Center for Integrative Medicine, School of Medicine, University of
California, Irvine, Costa Mesa, California, USA
4Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore,
Maryland, USA
*Corresponding Author: lxlao1@hku.hk
mechanisms through which acupuncture may modulate
insomnia by acting on hyperarousal of the ANS and
regulation of HPA activation.
Inhibition of sympathetic activity
Acupunc ture is believed to modulate sympathetic and
parasympathetic ac tivity, as evidenced by its effects on
the regulation of cardiovascular function, including lower-
ing blood pressure in patients with hypertension (12) and
decreasing the heart rate as well as skin blood ow in healthy
subjects (13). An experimental study in healthy subjec ts
found that needling on the Sishencong (EX-HN1) acupoint,
commonly used in the treatment of insomnia, decreases
the low-frequency component of the hear t rate variability
spectrum, which is an indicator of the balance between
sympathetic and parasympathetic activities, suggesting that
acupunc ture enhances cardiac vagal tone and suppresses
sympathetic activity (14). Acupuncture may alleviate insom-
nia symptoms and signicantly decrease heart rate variability
in poststroke patients (15), suggesting that improvement in
subjective insomnia symptoms result s from reducing sympa-
thetic nervous system activity.
The pathophysiological pathway by which acupuncture
may facilitate the sleep-wake transition through inhibition of
sympathetic activity is not fully understood. Nevertheless,
the effects of acupuncture on the excitator y cardiovascu-
lar reexes may provide some hints. A long-loop pathway
involving the arcuate nucleus (ARC) and ventrolateral
periaqueductal gray (vlPAG), that modulates cardiovascular
sympathoexcitatory bulbospinal neurons in the rostral ven-
trolateral medulla (RVLM) has been suggested as a possible
explanation for an acupuncture mechanism. Electroacupunc-
ture stimulation at acupoints Neiguan (PC6), a commonly
used acupoint for insomnia, and Jianshi (PC5), activates ARC
neurons in the ventral hypothalamus, which, in turn, provides
excitatory projections to the midbrain vlPAG. Activation of
neurons in the vlPAG stimulates cells in the raphe nuclei,
which inhibit activity of cardiovascular premotor sympatho-
excitatory neurons in the RVLM via endorphin, enkephalin,
GABA, and serotonin (16). Since insomniacs apparently show
elevated cardiovascular activit y associated with ANS hyper-
arousal, the effects of acupuncture on sleep may involve this
long-loop pathway.
Regulation of HPA axis
Acupunc ture may improve sleep by regulating the HPA
axis. Studies have shown that acupuncture reduces adreno-
corticotropin hormone (ACTH), also known as corticotropin,
and corticosterone/cortisol levels in animal models of stress
(17) and in human subjects (18). However, precisely where in
the HPA pathway acupuncture exerts its effect is not clear.
More recently, an experimental study found that electroacu-
puncture at Zusanli (ST36) prevents chronic stress-induced
activation of the HPA axis, as well as elevated sympathetic
nervous system-related adrenal NPY (19). The study found
that cor ticotropin-releasing hormone (CRH) levels were
signicantly reduced in acupuncture-treated animals. Find-
ings suggest that acupuncture inhibits the HPA axis activity
at or above the level of paraventricular nucleus (PVN) CRH,
thereby preventing stress-induced elevations in circulating
Possible mechanism of action
FIGURE 1. The possible pathway describing the effect of acupuncture on
hypothalamic-pituitary-adrenal (HPA) activation. The stimulation of Zusanli
(ST36) inhibits the HPA axis at or above the level of the paraventricular
nucleus (PVN) through corticotropin-releasing hormone (CRH), thereby
preventing the stress-induced elevations in circulating adrenocorticotropin
hormone (ACTH) and corticosterone levels. It may also prevent increases
in stress-induced adrenal neuropeptide Y (NPY) messenger RNA (mRNA)
expression.
FIGURE: ADOPTED FROM THE PUBLIC DOMAIN AND FREEDIGITALPHOTOS.NET
Authors:
Wing-Fai Yeung1,
Ka-Fai Chung2,
Stephanie Tjen-A-Looi3,
John Longhurst3,
Lixing Lao1,4*
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