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Some Important Considerations on Animal Studies With Respect to Research

in Ayurveda

Article · March 2018

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 Spreading
Knowledge

appropriate model and sample size. Here are

Some Important Considerations on Animal Studies some important considerations:
• To explore efficacy of the drug, choice of
With Respect to Research in Ayurveda appropriate animal model is essential.
• Appropriate positive and negative controls
P.V. Deshmukh1 *, S. B. Jamadagni1, S.N. Upadhyayl, J. Hazra1 may be used. Various positive controls
Abstract: Ayurveda is a goldmine for researchers. Unfortunately very few researches are acting by different mechanisms will throw
planned with a comprehensive approach. The present situation does not permit mere in-vitro light on possible mechanism of action of
tests to ensure the safety of the drug. Hence, it is very important to give thorough attention the drug.
before starting the research on ayurvedic drugs. Apart from opinion of ayurveda practitioner • After knowing possible mechanism of
detailed discussion with pharmacologist, chemist, biologist statistician and pathologist will help action more focused research to confirm
in deciding appropriate model and sample size. it is always better to be precisely knowledgeable the findings will help in validating the
in modern terms instead of believing merely beca"Jse it is stated in literature. It is necessary to claim.
treat Ayurveda drug research as New Drug Discovery. • Further consideration comes to dose of the
drug. The dose given in ayurvedic
Keywords: Considerations, Animal Studies. Toxicity, Ayurveda literature can be validated based on
efficacy and toxicity studies. Although if.
INTRODUCTION Phase I clinical trial Le. before entry of drug rationale for dosage is not available it can
One properly planned, performed and into first human being it is necessary to know be judged based on available evidences.
presented research can help as a ladder in possible target organs of toxicity in animals, The anupana given in ayurveda literature
development of the science. Th,s is very true in the No Observable Effect Level and No has to be studied thoroughly so as to
case of research on Ayurvedic drugs. In case of Observable Adverse Effect Level of the drug. obtain data regarding its efficacy. By
majority of ayurvedic drugs it is still not In-vitro studies till date could not gain faith of efficacy testing, qualitative response can
known how these drugs bring about the action, the regulatory agencies. Animals studies is the be judged but consideration should be
whether they bring out action by any specific only option where conditions can be simulated given to dose of the drug. If it is not
mechanism or not? How they are metabolized, to human being and biologic response can be possible to validate then we must check
excreted and distributed? Currently available obtained. modern drug development as a tool in
literature is so short on this aspect that it There are also reports of failure of animal ayurveda drug development.
remains as challenge to the sdentists working studies to extrapolate the risk factors to Studies in animals by using usually
in this field. humans. E.g. Literature on Thalidomide described methods of testing may not be
Many of the researchers prefer research in tragedy suggests that it had no apparent sufficient to understand the mechanisms. A
animals and by literature survey it can be toxicity or additive effect in adult human or detailed approach, focusing mechanistic
easily understood whether consideration to animals at therapeutic dose (Rogers and studies should be applied. In deriving dose
important points is given or not. The journals Kavlok, 2003). But this say is about modern response relationship following assumptions
- have set straight rejection criteria's to avoid
superfluous publication. They may reject the
drug development There are
physiologic differences between species and
many are generally made:
1. The response produced is due to the drug.
articles bu,preventing un-publishable work in strain. These variations have some degree of 2. There is some mechanism by which drug
science is difficult. Journal of impact on study conduct and interpretation of produces its response L e. there is some
Ethnopharmacology in its guidelines to results. There are pharmacokinetic differences molecular target which responds to the
authors has clearly stated Rule of S. By reading in animals. Underlying disease in certain drug and the response varies when dose
it we can come to know what kind of research species and strain can make difference of varies.
is not required in the field of Ethno- observations. Unfortunately very little 3. The magnitude of this response is directly
pharmacology. In case of Ayurveda it is highly progress has been made in harmonising the related to the dose.
essential to discuss what is not expected in scientific basis for selection of appropriate 4. The response is quantifiable and
research. In this article we have discussed model (Svendsen, 1994). Some claims say the expressible upon reproducing the
some of the considerations which need to be ayurvedic drugs in human being are safe and conditions. Le. response can be measured
reviewed before using animals while studying the dosage is based on prakriti of that person. based upon biological parameters viz.
Ayurveda. Ayurveda system of medicine is moreover a mortality, body weights, hematological •
personalised system of medicine. This is not and biochemical parameters and upon
Why animal studies are necessary supported by any valid reference. However, it histopathological observations.
This is one of the frequently asked questions is always better to be precisely knowledgeable
that whether it is essential to perform toxicity in modern terms instead of belieVing merely Toxicity studies: Last in Pre-Clinical but
studies in animals. This is a many fold debate. because it is stated in literature. It is necessary Never the Least
Modern drug development will never accept a to treat ayurveda drug research as New Drug All regulatory studies when consider a drug
drug without animal studies. Since, there are Discovery. Here we know only the therapeutic for marketing approval they need toxicology
reports that ayurvedic drug contains metals use of the drug by classical literature but data. The present situation does not permit
above permissible limit (Saper et al. 2004)
many regulatory agencies are pressing hard on
unaware of other essential data about it. mere in-vitro tests to ensure the safety of the
drug. in-vivo toxicity studies are performed to
-
safety data of ayurvedic drugs. Before starting Considerations before Initiating Research evaluate target organs, establish No Observed
It is very important to give thorough attention Adverse Effect Level or No Observed Effect
before starting the research on ayurvedic Level. There are two basic principles of
1 National Research Institute of Ayurveda for
drugs. Apart from opinion of ayurveda performing toxicity studies (Eaton and
Drug Development CCRAS, Department of AYUSH,
Ministry of Health and F.w.. Govt. of India 4-CN practitioner detailed discussion with Klassen, 2003):
Block, Sector V, Bidhannagar, Kolkata-700091 pharmacologist. chemist, biologist statistician
and pathologist will help in deciding

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• ---
 •
1. Effects produced by a compound in
laboratory animals when properly
quantified are directly applicable to
human.
2. Exposure to toxic agents in high doses is
necessary and valid method of discovering
possible hazard to human health.
Guidelines for toxicity studies clearly
indicate the upper limit of dose should
produce some signs of toxicity. Hence, the
approach of extrapolating the dose based on
dose conversion table will not serve the
purpose. In establishing dose levels for toxicity
studies it is necessary to start from limit tests
and then pilot studies. There is need to check
response of each and every system in body
hence, toxicity studies must be performed
considering all possibilities. E.g. while
performing toxicity study of bhasmas e.g.
Kasisa Bhasma then it is necessary to evaluate
iron toxicity as one of the positive controls.
Rasamanikya bhasmas which contain mercury
the toxicity should be compared with mercury
compound and consideration should be given
to eye, central nervous system, lungs, GIT and
kidneys as target organs. It is also necessary to
conduct reproductive toxicity study because
fetuses exposed to mercury suffer from
toxicity. Also, it is necessary to verify
reversibility of the toxicity since, heavy metals
toxicity gets reversed after withdrawal of the
exposure.
Moreover, doing merely acute, sub-acute
and chronic toxicity studies will not be a
sufficient data. It is suggested to perform
genotoxicity and reproductive toxicity on
priority but other toxicity testing may also be
done based on intended use of the drug.
Important Considerations while
extrapolating the data from Pre-clinical to
Clinical:
After performing the pre-clinical toxicity
studies obviously the observations are to be
extrapolated to human being. There are many
physiological and morphological differences in
human and laboratory animals. Certain
important morphological differences are:
1. Rats do not have gall bladder.
- -
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•
2. Rats and mice have a non-glandular
portion of stomach unlike dogs and
primates.
3. Placentation differs significantly among
laboratory animals and human.
4. The dogs have different ocular structure
than rabbit
There are many physiological differences
which are very difficult to record and report
and insuffident to explain why drug behaviour
changes in different systems. Few of the
reported differences are:
1. The BMR of most of the laboratory animals
especially rodents is higherthan human.
2. There is species difference in the rates of
GI absorption of various compounds.
3. Dermal absorption differ in various
species ego skin of pig simulate human
skin.
Problems which arise while extrapolating
the laboratory results into human of an
ayurvedic drug are first the ayurvedic
medicine is based on principles of vata, pitta
and cafa. Secondly, anupana given in ayurveda
literature may not be applicable to laboratory
animals. However, if we consider an ayurvedic
drug as some 'unknown chemical' then
preclinical toxicity data is useful to understand
target organ of toxicity of that 'chemical.
CONCLUSION
Ayurveda is a goldmine for researchers. Very
few researches are planned with a
comprehensive approach. Many research
articles explain only statistical relation
between the available extract, herbal or
ayurvedic preparation and animal response or
preventive effect of the above which does not
signify that these are drugs. This only indicates
that there is some efficacy and should be given
mechanistic approach to make it into a drug.
Unnecessary usage of animals and production
of non-target oriented results are the true
problematic outcomes of this mad-rat race of
research. Very few researchers have that
vision, facility and ideas of exploring and
describing the mechanism behind the action.
Drugs can be used as a tool to understand
basic changes taking place when drug is
administered for specific purpose.
,
Issue 2
Spreading
iY\vevrh Knowledge
If we see recent past there are many
controversaries about using ayurveda drugs,
merely saying these drugs do act by some
unknown, magic mechanism which is still
uncovered is blight to all the scientists in India
working in this field. Also researchers need to
think they are to contribute to the science and
not just the degree followers. It is also
responsibility of the journal editors to
encourage more science based articles.
Preparing a compiled document of
publications on each and every ayurvedic drug
so as to avoid repetition of work and wastage
of funds. If we say there is a system then it
should come out as proven alternative system
of medicine.
The practice of medicine has undergone
profound changes during last 40 years but
Ayurveda system of medicine is still lacking
the scientific backup. Emerging technologies'
can now help in understanding the underlying
mechanisms only if they are tackled to use in
Ayurveda.
REFERENCES AND NOTES
1. Cassarette and Doul1's Essentials of TOXicology,
McGraw hill publication, USA 2003
2. M.A. Holliday and T. j. Eagan 'Renal function in
man, dog and rat', Nature 1932, 193,748-750
3. E.I. Calabrese 'Gastrointestinal and dermal
absorption: interspecies difference drug Met3b.
Rev. 1984,15, 1013-1032
4. Comparative TOXicology, eds. Glenn Sipes,
Charlene A McQueen, A. Joy Gondalfi, Vol. 2
5. Saper Robert P., Kales Stefanos N., Paquin Janet,
Burns Michel J., Eisenberg M. David., Davis B.
Roger, Phillips S Russel Journal of American
Medical Association, December 15, 2004 Vol.
292, No. 23 2B6B-2873
6. Rogers John M and Kavlok Robert J.
Developmental Toxicology, in Casarett and
Doull's Essentials of TOXicology, Eds. Curtis
Klassen and John B. Watkins JIJ chapter 10,
Edition J, 2003 pp 148
7. Eaton L. David and Klassen Curtis D. Principles
of Toxicology in Casarett and Doull's Essentials
of TOXicology, Eds. Curtis Klassen and John B.
Watkins JIJ chapter 10, Edition I, 2003 pp. 16
8. O. Svendsen in Handbook of laboratory animal
science eds. P Svendson and J Hau, CRC press,
Boca Raton F L, 1994 Vol.lI part4.
20l0eplOO. CCC: $10 © Inventi lournals (P) Ltd
Published on Web 27/07/2010, www.inventl.ln