The Future of Safety Pharmacology Studies for Human


Dec 3, 2012 (4 years and 6 months ago)


The Future of Safety Pharmacology Studies for Human Pharmaceuticals

By Felix O. Omoruyi


The study of pharmacology involves the evaluation of the effect of a compound on any
biological target. Safety pharmacology is the

step by step investigation of a drug for
activity to stimulate, potentate or inhibit the activity of physiological or pharmacological
responses or interaction with another drug in vitro or in vivo. Safety pharmacology
studies are designed to assess the po
tential adverse effects of a compound on the
physiologic function of one or more organs, or organ
systems, in prepared models that
have been shown to be relevant to human (healthy or sick).

Many people today are turning away from convectional drugs to he
rbal medicine and
there are claims and counter claims on the safety of both convectional drugs and herbal
medicines. However, people are very skeptical about the safety of herbal medicines and
new drugs, safety is therefore key to the future of convectiona
l drugs in the global
Pharmacological studies have been performed worldwide for many years as part
of the non
clinical evaluation of pharmaceuticals for human use. There are however, no
internationally accepted definitions/recommendations on the de
sign and conduct of
safety. The term

safety pharmacology studies

first appeared in ICH

Timing of Non
clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals


S6 Preclinical Safety Evaluation of Biotechnology
Derived Phar

as studies
that should be conducted to support use of therapeutics in humans.

What is a "Safe" Drug?

It is important to note that no drug in the world is totally risk free. There is risk involve
every time a drug is taken. Dr. William Comano
r says “Drug safety means finding the
right balance”. What Comanor is saying here is that one need to weigh the risk of taking a
drug against the benefit that may accrue to the usage and this constitutes exactly how
drug safety is defined by FDA. Note howe
ver, that FDA's determination that a product is
safe does not necessarily suggest an absence of risk. Human pharmaceutical is declared
safe by FDA if the clinical significance and probability of its beneficial effects outweigh
the likelihood and medical im
portance of its harmful or undesirable effects. In other
words, a product is considered safe if it has an appropriate benefit
risk balance for the
intended population and use.

Safety Pharmacology

The non
clinical risk assessment of new therapeutic
agents intended for human use has
often times been based on results from
in vivo

toxicological studies, together with
in vitro

in vivo

studies of genotoxicology. The key issues in safety pharmacology are, to
determine what is to be done and the appropr
iate stage of the drug development process
to do it. The objectives of safety pharmacology are to detect functional changes
in vivo

in vitro

that is likely to be of importance in clinical testing of new drugs.
Therefore the emphasis of the Safety Ph
armacology is to focus on those effects that are
difficult to detect within toxicological studies. The side
effects receiving most attention
today include those that manifest as cardiovascular dysfunction, such as hypotension,
hypertension, tachycardia, ca
rdiac arrhythmia or alterations in the central nervous system.
harmacological effects vary among test substances. The following factors should be
considered in the selection and designs.

Those with effects that are related to the therapeutic class of the

test substance,
(example, proarrhythmia is a common feature of antiarrhythmic agents)

Adverse effects linked with members of the chemical or therapeutic class, but
independent of the primary pharmacodynamic effects (example, antipsychotics
and QT prolong

Ligand binding or enzyme assay data pointing to a potential adverse effects

Results from previous safety pharmacology studies such as secondary
pharmacodynamic and toxicologic studies.

Of note however, is that sufficient information may not alway
s be available to rationally
select or design the studies in accordance with the above points during early
development. A more general approach in safety pharmacology investigations could be
applied under such conditions.

In safety pharmacological studies
, vital organs or systems which are acutely critical for
life such as the cardiovascular, respiratory, and central nervous system are considered to
be the most important ones to assess. Organs like the renal or gastrointestinal system
whose functions are t
ransiently disrupted by adverse pharmacodynamic effects without
causing irreversible harm, are of less immediate investigative concern. Safety
pharmacology evaluation of these systems may be of particular importance when
considering factors such as the lik
ely clinical trial or patient population.

Dose Levels of Test Substance

In Vivo Studies

In vivo

safety pharmacology studies define the dose
response relationship of the adverse
effect observed. The time course such as onset and duration of response of t
he adverse
effect should be investigated, when possible. Comparison is generally between the doses
eliciting the adverse effect and the doses eliciting the primary pharmacodynamic effect in
the test species or the proposed therapeutic effect in humans. The
re are however
differences in pharmacodynamic sensitivity among species. Doses should therefore
include and exceed the primary pharmacodynamic or therapeutic range. In the absence of
an adverse effect on the safety pharmacology parameters evaluated in the
study, the
highest tested dose should be a dose that produces moderate adverse effects in this or in
other studies of similar route and duration.

In Vitro Studies

In vitro

studies are designed to establish a concentration
effect relationship. The range o
concentrations used should be selected to increase the likelihood of detecting an effect on
the test system. The upper limit of this range may be influenced by physico
properties of the test substance and other assay specific factors. In the abs
ence of an
effect, the range of concentrations selected should be justified.

Safety Pharmacology Core Battery

The purpose of the safety pharmacology core battery is to investigate the effects of the
test substance on vital organ functions. The cardiovas
cular, respiratory, and central
nervous systems are usually considered the vital organ systems that should be studied in
the core battery. The study of these systems is vital to establish that drugs for human use
are devoid of adverse effects on these orga

Cardiovascular System

The effects of the test substance on the cardiovascular system (blood pressure, heart rate,
and the electrocardiogram) should be assessed.
In vivo, in vitro

ex vivo

evaluations, including methods for repolarization and con
ductance abnormalities should
also be considered.

Central Nervous System

The effects of the test substance on the central nervous system (parameters include motor
activity, sensory/motor reflex responses, behavioral changes, coordination and body
ture) should be assessed.

Respiratory System

The effects of the test substance on the respiratory system should be assessed.
Respiratory rate and other measures of respiratory function should be assessed.

Supplemental Safety Pharmacology Studies

mental studies are meant to evaluate potential adverse pharmacodynamic effects
on organ system functions which are not addressed by the core battery.

Renal/Urinary System

The effects of the test substance on renal parameters such as urinary volume, spe
gravity, osmolality, pH, fluid/electrolyte balance, proteins, cytology, and blood chemistry
determinations such as blood urea nitrogen, creatinine, and plasma proteins should be

Autonomic Nervous System

The effects of the test substance o
n the autonomic nervous system e.g. binding to
receptors relevant for the autonomic nervous system,

functional responses to agonists or
in vivo

in vitro
, direct stimulation of autonomic nerves and measurement of
cardiovascular responses, bar
oreflex testing, and heart rate variability should be

Gastrointestinal System

The effects of the test substance on the gastrointestinal system such as gastric secretion,
gastrointestinal injury potential, bile secretion, transit time, ileal c
in vitro

gastric pH measurement should be assessed.

Other Organ Systems

The effects of the test substance on organ systems such as skeletal muscle, immune, and
endocrine functions should be assessed especially when there is a reason for
Safety of human pharmaceuticals has become very important that the evaluation of these
organs have implications in the future of conventional drug usage and the continued
global marketability of such drug.

Conditions under Which Studies Are Not N

Safety pharmacology studies may not be needed for locally applied agents where the
pharmacology of the test substance is well characterized, and where systemic exposure or
distribution to other organs or tissues is shown to be low. Safety pharma
cology studies
for cytotoxic agents require for the treatment of end
stage cancer patients may not be
needed prior to the first administration in humans. However, cytotoxic agents with novel
mechanisms of action require safety pharmacology studies. For bio
derived products that achieve highly specific receptor targeting, it is often sufficient to
evaluate safety pharmacology endpoints as a part of toxicology and/or pharmacodynamic
studies. Safety pharmacology studies could be reduced or elimi
nated for these products.
However, those products that represent a novel therapeutic class and/or those that do not
achieve highly specific receptor targeting require extensive evaluation by safety
pharmacology studies.

Timing of Safety Pharmacology Stud

Studies Prior to First Administration in Humans

The effects of a test substance on the functions listed in the safety pharmacology core
battery should be investigated prior to first administration in humans. Follow
up or
supplemental studies identif
ied as appropriate should also be conducted. Information
from toxicology studies adequately designed and conducted to address safety
pharmacology endpoints could result in reduction or elimination of separate safety
pharmacology studies.

Studies during Cl
inical Development

Additional studies may be needed to clarify observed or suspected

adverse effects in
animals and humans during clinical development.

Studies before Approval

Safety pharmacology effects on organ systems and others should be assessed
and safety
established before product approval. There should be a justification if such studies are not
necessary. Available information from toxicology studies adequately designed and
conducted to address safety pharmacology endpoints, or information from

studies, can support this assessment and replace safety pharmacology studies.

Application of Good Laboratory Practice (GLP)

It is important to ensure the quality and reliability of nonclinical safety studies. This is
normally accomplished thro
ugh the conduct of the studies in compliance with good
laboratory practice (GLP). It has to be emphasized that data quality and integrity in safety
pharmacology studies should be ensured even in the absence of formal adherence to the
principles of GLP. Whe
n studies are not conducted in compliance with GLP, study
reconstruction should be ensured through adequate documentation of study conduct and
archiving of data. Any study or study component not conducted in compliance with GLP
should be adequately justifi
ed, and the potential impact on evaluation of the safety
pharmacology endpoints should be explained. The safety pharmacology core battery
should be conducted in compliance with GLP. Follow
up and supplemental studies
should be conducted in compliance with
GLP to the greatest extent feasible. Safety
pharmacology investigations can be part of toxicology studies; in such cases, these
studies would be conducted in compliance with GLP.

However, primary and secondary pharmacodynamic studies do not need to be con
in compliance with GLP. Results from secondary pharmacodynamic studies conducted
during the compound selection process may contribute to the safety

evaluation. When there is no cause for concern, these studies need not be repeated in
mpliance with GLP. In some circumstances, results of secondary pharmacodynamic
studies may make a pivotal contribution to the safety evaluation for potential adverse
effects in humans, and these are normally conducted in compliance with GLP.

Regulatory To

The overall goal of here is to promote toxicology regulations founded on good science.
The aims of regulatory toxicology can be achieved by providing a forum for active
interaction between toxicologists from different disciplines and backgrounds
such as
government, academia and industry. This will facilitate the exchange of ideas between
toxicologists who have a common interest and the integration of new scientific
developments into risk assessment which will further ensure proper safety evaluatio

Safety Assessment of New Drugs

Seven out of 10 American consumers would prefer a drug that had been on the market
for 10 years or more over newer drugs, even if the co
pays were equal. The reason for
this according to reports is that many consumers thi
nk older and newer drugs are
equally effective, one in three (31 percent) believe newer drugs are less safe than older
drugs, according to The Medco Monitor(TM). This is certainly an indication that
consumers are becoming more safety conscious than ever be
fore. To circumvent this
hurdle in the human pharmaceuticals, more detailed safety evaluation of new drugs and
perhaps older ones need more attention from the regulatory authorities and the
pharmaceutical companies with adequate advertisements on the safet
y of newer drugs.
It is pertinent to note that there is an interesting division developing in the mind of the
consumer that makes a clear delineation between the safety of new drugs versus their
efficacy. In today’s world, consumers are not just only inte
rested in the potency of
drugs but safety now comes first against benefits that may be available with newer
medicines. It is now very clear that the safety concerns affecting specific drug classes
cast a long and dark shadow coloring the broader perception

of all new drugs, and how
consumers are willing to sacrifice effectiveness to ensure their own safety.

A number of high
profile, widely used prescription drug classes have drawn

increasingly intense scrutiny. Food and Drug Administration (FDA) in 2003
issued a
public health advisory which links antidepressant use among children to suicidal
tendencies. The FDA followed with a formal warning and call to action in the fall of
2004, and the implementation of the black box warnings on the class of medication
for pediatric patients. FDA advisory panel also held hearings on the safety of COX
inhibitors and other pain relievers, and requested that manufacturers require stronger
warning labels regarding cardiovascular and gastrointestinal risks. This again p
oints to
the seriousness of safety with regard to human pharmaceuticals in our modern world.
The survival of the pharmaceutical industries compared to other methods of treatments
is dependent on how vigorous and effective safety matters are handled with re
gard to
new human pharmaceuticals.

Consider the following report with regard to newer drugs:

third of respondents felt that newer drugs were more effective than

drugs that have been on the market for 10 or more years.

Only one in 10 adults ove
r the age of 59 (11 percent) felt that newer

drugs were safer than older drugs.

Women were more likely than men to question the safety of newer drugs,

and were more likely than men to perceive that newer drugs were less

effective than
older drugs.

More than 80 percent of baby boomers (ages 40

58) were familiar with

the drug safety issues associated with COX
II inhibitors

a significant

impression reflecting the high rate of utilization for the medicine in this age


The Expectations of Regulatory Authorities

The Federal Regulations (US) that an Investigational New Drug (IND) application must
be filed (21

Part 312) states that preclinical toxicity studies (in compliance with
Good Laboratory
Practices (GLP) regulations) should be conducted to determine the
therapeutic compound’s safety for the proposed clinical trial. The duration of a planned
clinical trial and the period of exposure in humans are key factors in developing the
nonclinical tes
ting program. These parameters will impact the type and duration of the
nonclinical studies needed to support the proposed clinical trial and, ultimately, the
clinical development program. However, for single
dose clinical trials conducted in the
onsiders data generated in single
dose toxicity studies adequate support
(provided that histopathology was conducted). The goal of Exploratory INDs allows
sponsors to dose humans at subtherapeutic doses for the purposes of identifying a lead
candidate for
further development based on the pharmacokinetic (PK) profile, including
biodistribution via imaging applications, as well as a further understanding of the
relationship between the mechanism of action and disease treatment. As the development
program move
s forward into later
stage clinical trials, the duration of a given trial will be
dictated by the disease state and new efficacy data that will have been generated in
previous trials. To support a proof
concept trial in patients, the necessary duration
nonclinical studies should be proactively identified and conducted to expedite
development and avoid regulatory delays.

Safety Assessment Goals

The primary goals of nonclinical safety evaluation in early drug development for a new

to assist in id
entifying an initial safe dose and subsequent dose escalation schemes
in humans.

to identify potential target organs for toxicity in humans, and whether such
toxicity is dose
dependent and/or reversible.

to identify safety parameters for clinical monitor

It is also very important to determine the pharmacological and toxicological effects and
mechanisms, not only prior to the initiation of human studies, but throughout the clinical
development and post marketing.

How Safe Are America's Medicines?

f note however, is that FDA drug review system has since early 1960s emphasized
extensive and carefully reviewed in pre
approval clinical trials. Not every country has an
FDA or effective regulatory set up making drugs in such countries to be marketed more

quickly leading to difficulties with drug safety. Political pressure should not compromise
safety because of the consequences associated with unsafe human pharmaceuticals.
Political pressure should not be allowed to push FDA into moving drugs through the
review process more quickly as has been the case since the late 1990s. In the late 1980s,
AIDS activists frustrated by the FDA's approval process demonstrated in favor of more
rapid drug approval. Other patient
advocacy groups and the pharmaceutical indust
favored rapid drug approval which led to the 1993 Prescription Drug User Fee Act.
PDUFA, as it's called, changed the rules of the game. Under PDUFA, drug companies
pay a hefty fee to submit new drugs for approval. That money is used to hire a new FDA
viewer. In return, the companies get much faster FDA action. This is both good and
bad, Comanor says. "There are costs to our society from delaying the introduction of
helpful drugs and testing them too thoroughly. Extra testing means delay. People die
n there are delays”, he says. "And there are costs to society from too rapid drug
approval. Drugs are powerful things and we don't always know the results of giving them
to very large numbers of people for a long time. People die as a result”. It is impor
tant to
strike exactly the right balance between timely approval and safety. The future of human
pharmaceuticals vis
vis safety lies in allowing FDA and other regulatory authorities to
function independently without unnecessary interference from any pres
sure group.

FDA should remain committed to safety and public health but should not create
unnecessary bottlenecks for new drug approval. To improve safety FDA announced the
following initiatives to improve safety:

The FDA asked the independent Institute
of Medicine to evaluate the U.S. drug
safety system. A major focus of the study will be on how best to monitor the
safety of approved drugs after they reach the market.

Initiation of a program that will referee differences of opinion among FDA

The organization of workshops and advisory committee meetings which will
bring together experts

from federal agencies, universities, the pharmaceutical
industry, and the medical community

to discuss drug safety issues.

Herbal Safety Issues

Asarum is

among the first herb learned in many parts of the world. Asarum has a long
history of use among Native Americans, and it is described as a stimulant, carminative,
diuretic, and diaphoretic. Asarum is sometimes added to cough mixtures and used in the
ic coughs to aid expectoration. It is usually grouped into the category of warming,
relieving herbs, which are placed at the front of the Materia Medica guides. In
Oriental Materia Medica

it is said that asarum "dispels cold and wind, warms the lun
gs to
resolve accumulated fluids." Among oriental herbal practitioners, the indications for
asarum include: cough with dyspnea, sinusitis, rheumatoid arthritis due to wind and
dampness, toothache retention of phlegm and fluid, general coughing. So far asar
um has
not been banned in any country and no concern has been raised about it use. Herbal
guides do not list it under the main headings as toxic or even slightly toxic. The positive
view of herbs and their safety began to crumble during the past few years.

herbal patent medicines from the Orientals have been found to contain heavy metals and
unknown toxins which are of safety concerns. There is general fear today in the use of
Chinese herbs. There are claims among some doctors that herbs have dama
ging effects on
the liver and kidney and thus warn their patients to avoid their usage. These warnings are
often supported by articles in the medical literature that are alarming which may not be
mere spontaneous attack by the medical profession against an

alternative healing system.

Although there are calls for the elimination of potentially harmful herbal materials and
establishing better controls over all herbal products, their safety regulation is a difficult
one. The demand for safety has its own haza
rds, which must be dealt with in a manner
that effectively improves the human condition. It is known fact that nothing taking in the
body of human is completely safe. Pure water for example becomes toxic at a high dose
because it dilutes the body's mineral

stores when too much of it is consumed. In the
absence of absolute safety, it is essential to become more familiar with the safety issues
that exist, and also to determine one's own tolerance for questionable safety.

Internet versus Safety issues

ng information in our present world has become very easy with the advent of
internet and many of the information fed to the public are not truly correct. Most
information fed to the public via internet is taken out of context. This is indeed giving
concerns new significance. Astragalus was one of the first Chinese herbs to
become widely known after the introduction of professional Chinese herb prescription in
the U.S. It became popular because of its immune
enhancing properties that had been
ed not only in China but also in the U.S. When some individuals who were
prescribed astragalus by an acupuncturist or other natural health care provider then asked
their physicians about it, considerable alarm was generated. The physicians did not have
ess to Chinese medical books, but when they turned to American books about herbs,
they readily found reference to astragalus. What they found was that astragalus poisoned
cattle and other livestock. They came back to warn their patients that they had been
as a very toxic herb. The flaws in the literature drove a wedge between the herbalists and
doctors, with patients caught in
between. What was found in the American literature was
true: astragalus, known as "loco weed" because of the bizarre behavior

of animals after
they consumed it, has poisonous leaves. But, the Chinese herb, obtained from the roots of
a different species, did not contain the poison in the leaves. The situation is, in fact,
identical to that with potatoes and tomatoes. People can e
at the food portion of the plant
regularly without any concern for their safety, but the leaves of the same plants are highly
toxic and can cause severe reactions and deaths. A person not familiar with potatoes and
tomatoes looking up their botanical name,

, would be horrified at the toxicity
described in the literature.

In our current information age doctors and patients are able to scan a vast literature.
Much information available there about herbs focuses on their harmful effects from

animal studies. In the German book called the “
Chinese Drugs of Plant
most of the analysis of the pharmacology of asarum is devoted to the
carcinogenicity studies of safrole. This is usually the information that comes up on an
international liter
ature search. Pharmacological studies performed in China on positive
effects of the herb (such as on cough) are rarely seen in the abstracts that are available to
researchers. Therefore, when a patient or physician looks into the ingredients of a
d formula and they search for information on asarum, the results may not be

Limitations in the Use of Herbs

It important to note at this juncture, that all herbs are toxic at some dosage level including
convectional drugs. Also, most herbs cont
ain ingredients that can be shown to be
carcinogenic or mutagenic in a laboratory test. We cannot reject herbal use based on the
content of an individual ingredient or laboratory evaluations that involve massive
overdosing of the herb. Consider aristolochi
c acid, it has been proposed recently that
even small amounts can be problematic in susceptible individuals, making it difficult to
find an acceptable dosage level whereas safrole and other allylbenzenes that may be
mutagenic or carcinogenic (in animals),
may be of limited concern for human
consumption and would not cause one to avoid a herb altogether. The way forward for
the use of asarum will be to obtain material that is free from aristolochic acid so it can
continue to be utilized. The removal of what
is perceive to be the causative of toxicity or
raise safety concerns is key for the continued future usage of asarum and other herbs.

The American Herb Products Association (AHPA) has recently recommended that herb
product manufacturers avoid all herbs con
taining pyrrolizidine alkaloids because they
accumulate in the liver if high enough quantities are taken and results from laboratory
animal studies show them to be carcinogenic. Such recommendation will limit the herbal
use because pyrrolizidine alkaloids
are widely distributed in nature. The approach of
either banning herbs or making them unmarketable because of the inclusion of a
at any dosage
may not be the right way to go. Certainly, the approach of this
nature help to protect the public from
potential dangers or actual dangers and it gives the
impression that by eliminating a few herbs one can make herbal remedies safe. However,
such safety is only relative. The question that arises is how many herbs will be eliminated
before one determines th
at herbal medicine is no longer a separate therapeutic interest?
Will it instead be incorporated into the realm of drug therapy where there is plenty of
safety testing and the adverse effects are quantified and put on the warning label? If so,
we may be le
ft with a few beverage herbs and the rest being sold as drugs. The probable
thing to do is to carefully establish the dosage that is safe and ensure compliance and an
in depth study of the constituent interactions when herbal products including new ones
e consumed and the safety of such products. As suggested earlier, the identification of
the toxic constituents and their subsequent removal or manipulation of the dosage that
will not compromise safety and effectiveness may be the way forward.

What Consume
rs Can Do About Drug Safety

The future of human pharmaceuticals also requires the active participation of consumers.
For example Buchanan advice to patients is NOT to stop taking any prescribed drug
without first talking to their doctor. Pharmacists, he s
ays, can answer many drug safety
questions. Patients can also do much to protect themselves. Safety is paramount in human
pharmaceuticals and so Buchanan has a short list of questions that consumers could ask
their doctor when he or she prescribes a drug:

What is this drug used for?

How long do I have to take it?

What dose should I take?

How often should I take it?

Are there any side effects I should be aware of?

If I have any of these side effects, what should I do about it?

Angell also advised pati
ents to be wary of new drugs. If an older drug will do the trick,
she says, use it before trying a newer, more expensive, and possibly less safe new drug.
Her advice:

Try not to take a drug that has been on the market for less than three years.

If your d
octor prescribes a newly approved drug, ask if there isn't a generic or
older drug that would be just as good. If your doctor says, "No, you need this new
one,' say "How do you know? What are you basing this on?"

"People have to give their doctors permiss
ion not to give them a prescription
whenever they walk out of the office," Angell says. "Ask your doctor, 'Are you
giving me a prescription or a free sample just to get me out of the office? Or
would it be better to talk with me about changing my lifestyle


The future of human pharmaceuticals is largely dependent on the amicable understanding
of the different stakeholders such as the pharmaceutical industries, the consumers, the
researchers, the regulatory authorities, the political groups et
c. Safety and effectiveness
should guide every step taken be the various interest groups. The regulatory authorities
like the FDA should not be seen as being too powerful but should be fully supported to
ensure that only safe and effective products eventua
lly find their way into the market.


Laura Alvey, spokeswoman, FDA, 2004.

Marcia Angell, Department of social medicine, Harvard Medical School, 2004.

Paul Barach, Jackson Memorial Hospital; Director, Center for Patient safety, University
of Miami/J
ackson Hospital, Miami, 2004.

Clyde Buchanan, Director of Pharmacy Services, Emory University Hospital, Atlanta,

William Comanor, Director, UCLA Research Program on Pharmaceutical Economics and
Policy, University of California, Santa Barbara, 2004.

avid B. Nash, Director, Office of Health Policy and Clinical Outcomes, Thomas
Jefferson University Hospital, Philadelphia.
FDA Review Process for New Drug
Applications: A Management Review
, HHS Office of Inspector General, 2003. FDA.

Angell, M.
The Truth
About Drug Companies: How They Deceive Us and What To Do
About It
, Random House, 2004.

Stephen M. Lindsey, Rheumatology department, Ochsner Clinic Foundation, Baton
Rouge, La,2004.

Hsu HY, et al., Oriental Materia Medica, Oriental Healing Arts Institute,
Long Beach,
California 1986.

Bensky D and Gamble A, Chinese Herbal Medicine: Materia Medica, Eastland
Press, Seattle, WA 1993 Rev. Ed.

Subhuti Dharmananda, Safety issues affecting Chinese Herbs: The Case of
Asarum, Institute for Traditional Medicine, Port
land, Oregon 2000.