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Reverse Pharmacological Correlates of Ayurvedic Drug Actions

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Reverse pharmacological correlates of ayurvedic drug actions*
actions*
A.D.B. Vaidya
Bhavan’s
Swami Prakashanand Ayurvedic Research Center
(SPARC),
Mumbai – 400 049. India
Received: 28.7.2005
Revised: 22.5.2006
Accepted: 30.5.2006
Correspondence to:
Ashok DB Vaidya
E-mail: bhaspa@bom5.vsnl.net.in
The human condition has been enhanced considerably by
those biochemists and pharmacologists who have applied the
scientific method to prove ancient myths and legends. For
example, the mystical powers of the snakeroot plant of India,
either ignored or ridiculed by scientists for decades, were
dispelled with the isolation and identification of its active
alkaloid.
– Richard E Davis
Sir Ram Nath Chopra (1882-1973) was a pioneer in the
field of experimental pharmacology of indigenous drugs of
India. Most of the medicinal plants he studied were in use, in
ayurveda, for thousands of years. At the Calcutta School of
Tropical Medicine, he pioneered a paradigm, a pace and a
pattern of research in studying the actions of medicinal plants,
which influenced an entire generation of pharmacologists,
pharmacists and physiologists in India. Fortunately, now, at
the Regional Research Laboratory (RRL) Jammu-Tawi, the
Chopra Archives are safely lodged for posterity. The collected
works, correspondence and materials may also serve as
valuable sources for a biography which can be commissioned
by the Indian National Science Academy, which had the
privilege of having Dr. R.N. Chopra as past president.
G.V. Satyawati, former Director General, Indian Council of
Medical Research (ICMR) has rightly emphasised, “The credit
for kindling the interest of Indian chemists and
pharmacologists in medicinal plants should rightfully go to
Sir Ram Nath Chopra, who has been acclaimed as the ‘Father
of Indian Pharmacology’”.[1]
*Based on the ‘Sir Ram Nath Chopra’ oration delivered by the author at the Annual Conference of the Indian Pharmacological Society on 10th January 2002
in Nagpur.
Special Article
Sir Ram Nath Chopra
While Sir Ram Nath Chopra and other West-trained
scientists were evaluating the effects of ayurvedic drugs and
plant extracts on tissues and animals, eminent vaidyas such
as Mahamahopadhyaya Gananath Sen were laying the
foundation of ‘Reverse Pharmacology’. The science of
integrating documented clinical/experiential hits into leads
by transdisciplinary exploratory studies, reverse
pharmacology further developed these leads into drug
candidates by experimental and clinical research. The
proposed approach is the new paradigm or a rediscovered
paradigm. “Rediscovered” because, even in modern
pharmacology, some of the major fundamental discoveries
evolved from plant effects in humans. Table 1 lists some
such historical examples of reverse pharmacology. The animal
models and/or mechanisms of such human effects often
provided the foundation of pharmacology. Novel phenomena
in healthy or ill humans still continue to occur and deserve a
critical study at different levels of biological organisation. This
can be an engaging and challenging task. It is possible that
such a quest for biodynamic mechanisms can generate new
disciplines in life sciences.
Ayurveda in India dates back to 3000 BC. It has a
connotation of revealed knowledge, complete within itself and,
as some say, it has hardly any need for research. Lokmanya
Tilak coined the term ‘Ayurvidya’ to liberate the creative and
research energies of this great heritage of healing wisdom.
India is a unique, democratic nation with a multi-population,
divergent lifestyles and pluralistic healthcare systems. Such
diversity offers an immense scope to observe and document
the effects of ayurvedic drugs, medicinal plants, dietary habits
and non-drug healing modalities. Reverse pharmacology
Indian J Pharmacol | October 2006 | Vol 38 | Issue 5 | 311-315 311
Vaidya
Table 1
Rediscovery of the paradigm of reverse pharmacology
Medicinal Clinical Experimental
plant effect correlate
Curare tomentosum Paralysis and death Neuromuscular
block [2]
Papaverum somniferum Analgesia Opioid receptors [3]
Physostigma venenosum Ordeal poison Anticholinesterase [4]
Cinchona officinalis Antipyrexia Antimalarial [5]
Digitalis purpurea Dropsy relief Na + ,K +-ATPase [6]
Salix alba Fever and pain relief Prostaglandins [7]
Strychnos nuxvomica CNS stimulant Glycinergic
receptors [8]
would initiate the research process from the robust clinical
base of documented therapeutic or other effects of plants
and formulations.
As an academic discipline, it comprises 3 phases:
1. Experiential robust documentation of clinical
observations of the biodynamic effects of standardised
ayurvedic drugs by meticulous record keeping.
2. Exploratory studies for tolerability, drug interactions, dose
range finding in ambulant patients of defined subsets of
the disease and para-clinical studies in relevant in vitro
and in vivo models to evaluate the target activity.
3. Experimental studies, basic and clinical, at several levels
of biological organisation, to identify and validate the
reverse pharmacological correlate of ayurvedic drug
safety and efficacy.
Such a creative research endeavour requires an excellent
teamwork by multisystem and multidisciplinary experts.
Reverse pharmacology, for drug development, has been
highly productive and cost effective in the recent past.
Globally, this approach has now generated greater interest in
ayurveda and Indian pharmacology.
Rauwolfia serpentina Benth (Sarpagandha)
Sen and Bose[9] not only showed the antihypertensive
effects of R. serpentina, but were also astute clinicians to
note certain side effects such as Parkinsonism, depression,
gynecomastia, acid peptic symptoms and so on. There was
almost a gap of two decades in discovering the
pharmacological basis of these actions. The storage vesicles
are rendered dysfunctional as a result of their interaction
with reserpine and the depletion of biogenic amines explained
the actions by mechanistic correlates.[10] As a spin off of the
side effects of R. serpentina, several new drugs were developed
such as L-dopa, antidepressants, bromo-ergocriptine, and
H 2 receptor blockers and so on. [11-13] The alkaloids of
R. serpentina, reserpine and ajmalcine, have served as
research tools in many experiments.[14]
However, there are still some unanswered questions. Does
reserpine have more incidence of depression and/or
extrapyramidal side effects than the standardised extract of
312 Indian J Pharmacol | October 2006 | Vol 38 | Issue 5 | 311-315
the plant? It is worthwhile to apply combinatorial chemical
methods for reserpine derivatives, which do not cross the
blood brain barrier, so that depression, a serious side effect,
is avoided. The uptake of norepinephrine by isolated
chromaffin granules, by inhibition of ATP-Mg2+ – dependent
mechanism has to be studied afresh at the transcriptional
level. Though reserpine is withdrawn globally, the extracts of
the plant are still used in ayurveda with a rationale of
ayurvedic pharmacodynamics. There is a need to conduct
pharmacovigilance on Sarpagandha ghanavati (water extract).
Psoralea corylifolia Linn (Bakuchi)
The use of this plant in treating leucoderma is well
documented in Rajnighantu (Nighantu – a compendium of
synonyms, properties and usages of medicinal plants) by
Pandit Narahari.[15] Besides the traditional and classical use of
P. corylifolia in treating leucoderma (shwitra kusta), there are
many other indications described in classic ayurveda texts
such as Bhavaprakash Nighantu.[16] These indications include
promoting skin health, hair growth, relieving attacks of
asthma and bronchitis and reducing inflammatory and
edematous conditions. Though the pharmacological
correlates of its pigment enhancing and antipsoriasis actions
have been studied, the other ayurvedic actions too deserve
attention.[17] The phytochemically induced covalent binding
of methoxalen to pyrimidine bases is responsible for its
therapeutic effect. The photoconjunction involves thymine
dimer adducts on the opposite strands of DNA. With the
current advances in human genomics, it would be worthwhile
to investigate whether such effects on DNA are localised to
the skin only and whether hair, retina and so on are also
affected. The other ingredients of the plant need to be studied,
in the reverse pharmacology mode, for the effects on edema,
asthma cough and anaemia. An overt focus on a single active
principle leads to the neglect of other active entities in the
plant. The external uses described in ayurveda deserve due
attention.[18]
Berberis aristata D C (Daruharidra)
The multiple uses and actions of the plant, Berberis
aristata (Daruharidra), have always intrigued pharmacologists
and clinicians. It is a topical antimicrobial par excellence in
ayurveda. Its use, as extract for eye drops in conjunctivitis, is
widespread. The active principle of the plant, berberine, has
been extensively studied. The activity of berberine against a
variety of organisms, including bacteria, viruses, fungi,
protozoa, helminths and chlamydia, has been
demonstrated.[19] Berberine has been shown to bind to DNA
and inhibit its cleavage.[20] There is an urgent need to develop
specially targeted drug delivery systems of berberine, for
topical and systemic antimicrobial use. Local anesthetic,
pigment inducing, enzyme inhibitor y, antihypertensive,
antipruritic and antipyretic activities have been reported with
berberine.[21, 22] Recently, the antiamnesic activity of berberine
has been reported.[23] Despite the diversity of activities, the
proper clinical documentation of the reverse pharmacology
of the plant has been neglected. Its beneficial effects on
Plasmodium vivax relapses have been reported by Gogte.[18]
But experiential documentation is urgently needed.

Picrorrhiza kurroa Royle ex Benth (Kutki)
Arogyawardhani (a herbo-mineral formulation) was
popularizsd by the late vaidya, Zandu Bhattji, for the treatment
of jaundice. A double blind trial with arogyawardhani, kutki
and placebo was conducted in viral hepatitis. Significant
hepatoprotective effects were observed with kutki, as a single
plant or as an ingredient in arogyawardhini. [24, 25] Later,
picrosides, the active principles of kutki, were also tested
in vivo and in vitro. Significant antioxidant as well as
hydrocholeretic effects were noted for kutki. These effects of
hepatoprotection in carbon tetrachloride (CCl 4) and
galactosamine models are considered the pharmacological
correlates of clinical actions. However, there is a need to study,
at the cellular and molecular levels, how the water outflow in
the biliary microcanaliculae is enhanced. The Central Drug
Research Institute (CDRI), Lucknow, has now developed a
cucurbitacin-free extract of P. kurroa (Picroliv®) which has
undergone Phase II trials.[26] The plant also inhibits passive
cutaneous anaphylaxis, as shown by Mahajani.[27]
Commiphora wightii Arnott (Guggulu)
Commiphora wightii (guggulu), which is a major ayurvedic
drug, is used widely in diverse formulations. A monograph of
all the major citations of its use has been published.[28] The
hypolipidemic effects of the plant were primarily discovered
through the reverse pharmacology mode. Satyavati,
Dwarakanath, Sukhdev and Nityanand have extensively studied
the hypolipidemic effect of C. wightii. The product has been
already marketed and widely used.[29, 30] However, the anti­
arthritic effects of C. wightii in clinical studies have been
relatively less investigated. We have sizeable experiential and
pharmacological studies with standardised guggulu
preparations. Phase I as well as long term and large dose
ambulant studies have been conducted. The ongoing studies
at the cellular and molecular levels have helped in evolving
pharmacological correlates of clinically shown actions.[31] The
side effects of the plant have also been documented. The
mechanisms of toxicity are yet to be studied. The plant can
offer a platform for technological innovations in
pharmaceutics, pharmacodynamics and pharmacokinetics.
The use of guggulu as a sacrificial incense (homadravya), in
sacrificial use (shantikarma), is currently being evaluated for
the antimicrobial effects of the volatiles. The topical
formulations of the plant demand unique dermato­
pharmacological reverse correlates. The different properties
of fresh and old gum guggulu, mentioned in ayurveda
literature, need additional clinical investigations both
experiential and exploratory.
Tinospora cordifolia Hook (Guduchi)
In his classic, ‘Indigenous Drugs of India’, Sir RN Chopra
wrote, “In spite of the fact that this plant is so extensively
used as a household remedy and also by the Tibbi practitioners
and much chemical work has been done, the pharmacological
action of the active principles isolated has not been worked
out. Efforts have not been made to carry out clinical trials
with a view to determine its effectiveness in dyspepsia and
other conditions”.[32] Bapat et al, have shown very interesting
results with T. cordifolia in patients undergoing gall bladder
Reverse pharmacology
surgery.[33] Recently, Chintalwar et al, have shown that the
polysaccharide fraction of the plant has a mitogenic effect on
the B-lymphocytes of the spleen.[34]
Clinically, the water extract of T. cordifolia has been used
to treat pyrexia of unknown origin, frequently, with gratifying
results. The pharmacological correlates of the antipyretic
actions at the molecular level[35] must be understood ayurveda
regards jwara (fever) as a disease entity and not merely as a
symptom. Exploring the mechanisms of the jwaraghna
(antifever) property of these plants and products such as
T. cordifolia gives us a totally different perspective on fevers.
The use of the plant, as a standardised formulation viz.
Immumod® (Wockhardt Pvt. Ltd.) 500 mg, b.i.d., before and
after cancer chemotherapy, has led to a reduction in the
incidence of nausea, vomiting and granulocytopenia.
However, there was no reduction in alopecia.[36]
Curcuma longa Linn (Haridra)
The wound-healing, antiinflammatory and antimutagenic
activities of turmeric have been demonstrated convincingly.[37]
However, its cancer preventive action needs to be more
actively pursued. Hastak et al, have shown its beneficial effect
in oral submucous fibrosis – a precancerous condition.[38] In
dimethyl benzanthracene (DMBA)-induced experimental
breast cancer, curcumin has shown a significant reduction in
carcinogenesis.[39] These effects are being investigated further
by our group. Recently, curcumin has been shown to reduce
the plaques in Alzheimer’s disease in the animal model.[40] It
has been stated that Indians have a lesser incidence of
Alzheimer’s disease due to a steady and regular consumption
of turmeric in their diet. The carminative effect of curcuma
oil was reported by Sir RN Chopra. He has also referred to a
marked diminution of the gastric acid secretion after fractional
test meals.[32] Hence, it may be worthwhile to study the effects
of curcumin, turmerone, and so on, on H1 and H2 receptors as
well as on the gastric H+K+-ATPase or the proton pump of the
parietal cell, by the reverse pharmacology path. Several
laboratories have demonstrated the antioxidant activities
of curcumin.
Saraca asoca (Roxb) Willd (Ashoka)
Sir RN Chopra, in his monograph on the S. asoca plant,
wrote, “This plant drug does not appear to have marked
therapeutic effects, though many clinicians appear to vouch
for its efficacy in menorrhagia and other uterine disorders”.[32]
Recently, Shringi et al, have shown with a formulation of
S. indica (Ashotone®), a reduction in menstrual blood loss, in
a distinct subset of menorrhagia, viz., ovulatory dysfunctional
uterine bleeding. [41] The broad claims of clinical efficacy in
ayurveda need to be fine tuned to the subsets of the disease
or a syndrome.
Panchvalkal (Five barks – Ficus bengalensis, Ficus
glomerata, Thespesia populnea, Ficus religiosa, Albizia lebeck)
Ranjan Bhatt and her students have shown the burn- and
wound healing activity of panchvalkal.[42] Joshi and colleagues,
at Bhavan’s Swami Prakashanand Ayurvedic Research Center
(SPARC), have shown some significant efficacy in
leucorrhoea. [43] A standardised novel formulation of
panchvalkal has already been developed by Viridis
Indian J Pharmacol | October 2006 | Vol 38 | Issue 5 | 311-315 313
Vaidya
Bio-pharma and clinical trials have shown its remarkable
wound healing activity. A further investigation into the
mechanisms of wound/burn healing by panchvalkal is needed.
The activity of panchvalkal against resistant microbes in vitro
offers unique advantages which need to be pursued clinically.
Azadirachta indica A. Juss (Neem)
The plant is a major medicinal tree of common household
use in India. It has currently drawn international attention as
an antifeedant for pests and due to the patent battle on one of
its active principles, azadirachtin.[44] Sir RN Chopra cites the
study conducted by Chatterjee with sodium margosate in
treating syphilis patients. The results, though positive, were
not comparable to the organometallic compounds.[32] But now
there is a need to explore the use of sodium margosate in
treating Lyme disease in vitro and in vivo animal studies
should precede clinical dose searching in Lyme disease.
In 1925, Chatterji successfully used a copper margosate­
ester in patients with head and neck cancer. This needs a
careful re-evaluation in the reverse pharmacology mode.[45]
Head and neck cancer constitutes a major problem in India.
Hence, any potentially complementary therapy is worth
exploring in these patients, where it could enhance the quality
of their lives.
Neem has shown antiviral activity against tobacco mosaic
virus, human papilloma virus and varicella (clinically).
However, the effects of diverse preparations of A. indica in
treating HbsAg (Hepatitis B surface antigen) carriers, HIV-
infection, Chlamydia trachomatis and so on, in humans, have
not been investigated adequately. Reverse pharmacology can
help in expediting such studies in a cost effective manner by
a network research and development. The activity of neem in
treating malaria also needs to be pursued.[46]
Therapeutic revolution through reverse pharma­
cology
Finally, one would like to re-emphasize that the pluralistic
healthcare system of India offers a virtual gold mine for novel
clinical observations, beneficial or adverse. A scientific
analysis of the de novo actions of natural products suggests
a need for the reverse pharmacology approach in the
development of safe, effective and acceptable therapeutic
agents. There is a need to create educational modules for
such an approach. Pharmacologists and clinicians need to
work in tandem for this novel route to drug development,
new uses of old drugs, more effective and safe derivatives of
active plant principles, new drug delivery and novel
bioenhancers of plant origin.
Indian contributions by reverse pharmacology to
therapeutic revolution will have to eventually integrate state
of the art high throughput screening, combinatorial chemistry
and effects of the old or novel compounds/plants on human
gene expression and proteomics. Sir Gananath Sen, Sir RN
Chopra, Dr. Rustom Jal Vakil and other doyens of Indian
reverse pharmacology will then be vindicated. It is my appeal
to the young generations, working in life sciences and
molecular pharmacology, to take up this challenge and put
India back on the world map of therapeutic discoveries.
314 Indian J Pharmacol | October 2006 | Vol 38 | Issue 5 | 311-315
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National Seminar on Drug Standardisation
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Place : Rajeev Gandhi Centre for Biotechnology, Jagathy,
Thiruvananthapuram, Kerala
Contact address:
Dr. A. Thankamma
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Drug Standardisation Unit,
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Thiruvananthapuram – 695 001. Kerala
Phone: 91-94475 53292
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