Reverse Pharmacology

1. 1. Dr. Ashutosh Tiwari Postgraduate Resident MD Pharmacology SAIMS Indore

12/06/2014
2. 2. Presentation Outline • Reverse Pharmacology: Definition, Scope & Phases •
Introduction • Drug discovery: current scenario • History: India • Status: India • Hurdles
• Future perspectives • Conclusion
3. 3. Reverse Pharmacology • Definition: – Reverse pharmacology is the science of
integrating documented clinical/experiential hits, into leads by transdisciplinary
exploratory studies and further developing these into drug candidates by experimental
and clinical research. • Scope: – The scope of reverse pharmacology is to understand the
mechanisms of action at multiple levels of biological organization and to optimize
safety, efficacy and acceptability of the leads in natural products, based on relevant
science.
4. 4. Key words • Drug Target: – Cellular/ molecular structures involved in the patho-
physiology of interest where drug –in-development is meant to act on • Hit: – Potential
activity at a chosen target • Lead: – Increased activity at a chosen target (potency) –
Reduced activity against unrelated target (specificity)
5. 5. Molecule • In this process ‘safety’ remains the most important starting point and the
efficacy becomes a matter of validation. Mice  Man • Reverse Pharmacology Path
Man  Mice Concept of Reverse Pharmacology • The traditional knowledge inspired
reverse pharmacology relates to reversing the routine ‘laboratory to clinic’ progress of
discovery pipeline to ‘clinics to laboratories’. • Conventional NCE Path Molecule
6. 6. Phases of Reverse Pharmacology • Reverse Pharmacology is a transdiscipline that is
comprised of three phases: • 1) Experiential phase – includes robust documentation of
clinical observations of the biodynamic effects of standardized 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 organization, to
identify and validate the reverse pharmacological correlates of Ayurvedic drug safety
and efficacy.
7. 7. Introduction • The ayurvedic knowledge database allows drug researchers to start
from a well-tested and safe botanical material. • With ayurveda, the normal drug
discovery course of ‘laboratories to clinics’ actually becomes from ‘clinics to
laboratories’ – a reverse pharmacology approach. • In ayurvedic medicine research,
clinical experiences, observations or available data becomes a starting point. • In
 conventional drug research, it comes at the end. • Thus, the drug discovery based on
ayurveda follows a ‘reverse pharmacology’ path.
8. 8. Traditional medicine Modern scienceModern medicine Reverse Pharmacology: Trans-
discipline A golden triangle consisting of ayurveda, modern medicine and science will
converge to form a real discovery engine that can result in newer, safer, cheaper and
effective therapies.
9. 9. Introduction • The mass screening of plants in the search for new leads or drugs is
vastly expensive and inefficient, but traditional knowledge offered better leads. • It is
estimated that over hundred new natural product- based leads are in clinical
development. • About 60% of anticancer and 75% of anti-infective drugs approved from
1981-2002 could be traced to natural origins. • It would be cheaper and perhaps more
productive to re-examine plant remedies described in ancient texts. • Reverse
Pharmacology can reduce three major bottlenecks of costs, time and toxicity.
10. 10. Introduction • Many active compounds from traditional medicine sources could
serve as good scaffolds for rational drug design. • Most of these compounds are part of
routinely used traditional medicines and hence their tolerance and safety are relatively
better known than any other chemical entities that are new for human use
11. 11. Drugs obtained by the reverse pharmacology path • Large numbers of promising
lead molecules have come out of Ayurvedic experiential base including: – Rauwolfia
alkaloids for hypertension, – Psoralens in Vitiligo, – Holarrhena alkaloids in Amoebiasis,
– Guggulsterons as hypolipidemic agents, – Mucuna pruriens for Parkinson’ s disease, –
Piperidines as bioavailability enhancers, – Baccosides in mental retention, – Picrosides in
hepatic protection, – Phyllanthins as antivirals, – Curcumines in inflammation, –
Withanolides, and many other steroidal lactones and glycosides as immunomodulators.
12. 12. Drugs obtained by the reverse pharmacology path • There are growing incidences
where the old molecules are finding new applications through better understanding of
traditional knowledge and clinical observations. For instance: • Forskolin an alkaloid
isolated by Central Drug research Institute (CDRI), CSIR, Lucknow a few decades ago
from Coleus forskohlii and phytochemicals from Stephania glabra, which were shelved
for a considerable time are now being rediscovered as adenylate cylase and nitric oxide
activators, which may help in preventing conditions including obesity and
atherosclerosis. • Antimicrobial berberine alkaloids are now being rediscovered as novel
cholesterol-lowering drugs working through different mechanism than statins. • Potent
anti microbial antirheumatic and cyclooxygenase inhibitory activities of phenolics,
catechols and flavonoids from an important Ayurvedic plant Semecarpus anacardium
have been reported as promising leads.
13. 13. Drug discovery: Current scenario • The pharmaceutical industry has historically seen
an incredible growth primarily due to the discovery of blockbuster drugs with the
 potential to generate over 1 billion US $ sales. However, recent trends indicate that this
model may no longer lead to high growth rates. • The average cost and time of
discovering, developing and launching a new drug is consistently increasing without an
expected corresponding increase in the number of newer, safer and better drugs. • As
compared to the previous years the numbers of New Molecular/ Chemical Entities
produced per company have declined. Moreover, the number of approvals for new
drugs has steadily declined from 53 in the year 1996 to 17 in 2007. • Clearly, drug
discovery is no more a game of chance or just limited to technology availability today.
The strategies that awarded success during the past may not guarantee success in the
future.
14. 14. Drug discovery: Current scenario • The industry is really facing a major challenge to
sustain and grow, which is resulting in many mergers, acquisitions or closures. • The
average cost of discovering, developing and launching a new drug in June 2008 was
inordinately high and represented a dramatic increase over the average cost from 1995.
• R&D expenses have risen from $2 billion in 1980 to over $40 billion in 2007.
Surprisingly, these increases have not led to a corresponding increase in the number
and efficacy of new drugs.
15. 15. Drug discovery: Current scenario • Drug discovery and development process
involves a 10-15 years of investigation period and investments of the order of US $ 1 to
1.5 billion • This extremely complex, technology based and capital-intensive process has
resulted in ‘target rich lead poor’ performance. • The pharmaceutical companies are
looking beyond conventional drug discovery and development approaches not only to
expedite the process, but also to ensure that safer and effective drugs could be
launched faster and sustained. • Natural product drug discovery, ethnopharmacology,
traditional, complementary and alternative medicines are re-emerging as new strategic
options. • The World Health Organization’s Commission on Intellectual Property and
Innovation in Public Health also has duly recognized the promise and role of traditional
medicine in drug development for affordable health solutions.
16. 16. History: India • Sir Ram Nath Chopra and Gananath Sen laid the foundation of
reverse pharmacology of ayurvedic drugs. • The credit for stimulating interest of Indian
chemists and pharmacologists in medicinal plants should go to Sir Ram Nath Chopra
who has been acclaimed as the ‘Father of Indian Pharmacology”. • Gananath Sen laid
the foundation of Reverse Pharmacology of medicinal plants by pursuing clinically
documented effects of Ayurvedic drugs. • Sen and Bose in 1931 demonstrated the
antihypertensive and tranquilizing effect of Rawolfia serpentina and also observed
unique side effects such as depression, extra pyramidal syndrome, gynecomastia and
peptic ulcer.
17. 17. History: India • Some promising work was undertaken almost 2-3 decades ago
through composite drug research program jointly conducted by Indian Council of
Medical Research (ICMR) and Council for Scientific and Industrial Research (CSIR) of
Government of India. • A cholesterol lowering drug Guggulipid was developed from
Commiphora mukul taking the lead from Ayurveda. • Drug Controller General of India
(DCGI) approved the drug for marketing in 1986. • Guggulipid is being manufactured
and marketed by Cipla Ltd, Mumbai under the brand name Guglip, however availability
of authentic raw material has remained a limiting factor. • A memory enhancer
developed from Bacopa monnieri by CDRI, Lucknow is also available in market.
18. 18. History: India • Recently, Nyctanthes arbor-tristis Linn has been shown to possess
antimalarial activity. The plant extracts are being standardized and studied
phytochemically as exploratory studies have already shown antiplasmodial effects in
vitro and disease modifying activity in patients. • This work has now been taken up by
the ICMR Advanced Centre of Reverse Pharmacology in Traditional Medicine, in
collaboration with the Centre of Molecular Parasitology at the Drexel University College
of Medicine.
19. 19. Reverse Pharmacology: India • Reverse pharmacology offers a major paradigm shift
in drug discovery. • Recently, India has amended the Drug Act to include a category of
phytopharmaceuticals to be developed from medicinal plants by Reverse Pharmacology,
with evidence of quality, safety and efficacy. These drugs will be distinct from traditional
medicines like Ayurvedic, Unani or Siddha. • Recognizing timely importance, the ICMR
has recently established an advanced center of reverse pharmacology with initial focus
on malaria, sarcopenia and cognitive decline. • CSIR, under the national network project
known as New Millennium Indian Technology Leadership Initiative (NMITLI) attempted
to bring industry and academia together right from the beginning where herbal drug
development projects on psoriasis, osteoarthritis, hepatitis and diabetes were
undertaken
20. 20. Reverse Pharmacology: India • Few case studies from India and abroad where the
reverse pharmacology approach has been attempted to expedite the drug development
process are presented here.
21. 21. Case studies Artemisinin— • The herb Artemisia annua has been used for many
centuries in Chinese traditional medicine as a treatment for fever and malaria. • In
1971, Chinese chemists isolated active substance - Artemisinin from the leafy portions
of the plant responsible for its reputed medicinal action. • Thus artimisinin and its
derivatives offer promise as a totally new class of antimalarials. • This discovery of
Artimisinin for malaria is a result of scientific work based knowledge from Traditional
Chinese Medicine (TCM) and presents best case for reverse pharmacology approach.
22. 22. Case studies Psoriasis— • One of the common dermatological diseases with no
preventive or curative therapy except the symptomatic management. • Under the
NMITLI project, Lupin Laboratories in India attempted development of a single plant
based oral herbal formulation through reverse pharmacology approach. • The drug
candidate (Desoris) is an herbal beneficiated extract of a single plant that has a novel
mechanism of action and effectively modulates the cellular function leading to psoriatic
lesion improvement.
23. 23. Case studies Psoriasis— • Extensive studies comprising fingerprinting, activity guided
fractionation, pharmacology, toxicology, efficacy, safety pharmacokinetics and
toxicokinetics helped the company filing an Investigational New Drug (IND) application.
• Lupin commenced the Phase I clinical trial in September 2004 and successfully
completed it. • This drug has been developed conforming to the US FDA guidelines for
botanicals and DCGI norms on new drug development. • This is expected to take 5-6
years and cost US $ 5 million as against routine drug discovery path of 10-15 years and
US $ 1-1.5 billion. • If successful, the resulting treatment with Desoris may cost US $ 50,
quite a step down from a new US $ 20,000 antibody injection treatment developed by a
western biopharmaceutical company.
24. 24. Case studies Parkinson’ s disease— • Ayurvedic physicians in ancient India first used
Mucuna pruriens seeds for the treatment of Parkinson’ s disease. • The dose used by
Ayurvedic physicians is small as compared to synthetic L-DOPA. • These observations
inspired scientists to further study and led to collaboration between academia and
Zandu Pharmaceutical Works from Mumbai. • Their team conducted series of
experiments on Mucuna to develop a natural drug for Parkinson’s disease.
25. 25. Case studies Parkinson’ s disease— • The United States Food and Drug
Administration have approved New Drug Application for clinical studies. • A Patent
Cooperation Treaty application has been filed as a novel method extracting Mucuna
prurients cotyledons and a composition for treatment of Parkinson’s disease. • Zandopa
is now approved by the Indian Food and Drug Administration. • This standardized, safe
and economical natural product can effectively replace synthetic L-DOP A formulations.
26. 26. Case studies Osteoarthritis— • For osteoarthritis herbal drug development NMITLI
project involved a network of 16 national research institutions, modern medicine
hospitals and pharmaceutical industries from India. • The project used traditional
knowledge guided platform where the base formulation was optimized with additional
ingredients to obtain desired therapeutic activities. • All the formulations were
manufactured under Good Manufacturing Practices in accordance with US FDA guidance
to industry for botanical drugs. • The preclinical evaluation was designed on the basis of
systems approach, wherein the assay battery involved targets relevant to inflammation,
pain, immunomodulation and chondroprotection (proteoglycan release, nitric oxide
 release, aggrecan release and hyaluronidase inhibition as markers) in human explant
model of OA cartilage damage. • This led to design of synergistic poly herbal
formulations that were found to be safe and devoid of any genotoxicity or mutagenic
activity.
27. 27. Case studies Osteoarthritis— • Short listed formulations entered series of
randomized clinical trials compared with known drugs glucosamine and celecoxib. •
Finally one best formulation was selected that led to one Indian and one Patent
Cooperation Treaty applications with a dossier of necessary data required for possible
regulatory submissions. • Thus, this project was completed in five years with
expenditure of over US $ 2 million. • This treatment may cost just US $ 25 a month for
patients with much better therapeutic benefits including chondroprotection that no
other modern drug offers. • Currently, CSIR is in the process of identifying suitable
industrial partner for further development, optimization, manufacturing, registrations
and marketing.
28. 28. Case studies • Thus, if safe and effective herbal formulations are developed in
accordance with stringent regulatory requirements on par with any modern drug, it is
hoped that the conventional skepticism against herbals may slowly wane.
29. 29. Reverse Pharmacology: Hurdles • Despite a vast potential and possibilities very few
success stories are available as of now • Most of the work in this field has remained
within clinics of traditional practitioners or confined to academic research laboratories
and not taken by industries that are strong in research and development • Majority of
the drug discoveries would not have been developed or their development would have
been delayed significantly in the absence of the scientific or technical contributions from
the pharmaceutical companies.
30. 30. Reverse Pharmacology: Hurdles • The pharmaceutical industry needs many more
successes like artemisinin and reserpine. Many promising leads like curcumins and
withanoloides are available but such R & D cannot ensue in isolation. • Best of public
and private sector partners comprising academia and industry should come together to
reap significant benefits from these seemingly low fashionable but highly gifted
explorations based on traditional knowledge.
31. 31. Future Perspectives • Many countries are becoming increasingly aware of the value
of their traditional knowledge • Global pharmaceutical industry is looking for innovative
solutions to their existing impasse on innovation deficit to re-activate and re-energize
discovery pipeline. • Therefore, innovative approaches inspired by traditional
knowledge will remain important to fast forward the discovery process and add new life
especially in the existing global economic environment. • It will be in the interest of
pharmaceutical companies, researchers and ultimately the global community to respect
the traditions and build on their knowledge and experiential wisdom.
 32. 32. Conclusion • Traditional knowledge and experiential database can provide new
functional leads to reduce time, money and toxicity - the three main hurdles in the drug
development. • These records are particularly valuable since effectively these medicines
have been tested for thousands years on people. • India with its pluralistic health care
system offers immense opportunities for natural product drug discovery and
development based on traditional knowledge and clinical observations.
33. 33. Conclusion • With Ayurveda, the normal drug discovery course of ‘Laboratory to
Clinics’ actually becomes from ‘Clinics to Laboratories’— a true Reverse Pharmacology
Approach. • Reverse Pharmacology approaches need to be developed further and
optimized as novel means for fast track drug discovery and development of newer, safer
and effective drugs

Rauwolfia serpentina Benth ( Sarpagandha)

Sen and Bose[9] not only showed the antihypertensive effects of R. serpentina, but were also
More Details
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 2receptor blockers and so on.[11],[12],[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 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-Mg 2+- 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 inhibitory,
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 witharogyawardhani, 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 guggulupreparations. 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 Tibbipractitioners 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
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 H 1 and H 2 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 Bio-pharma and clinical trials
have shown its remarkable wound healing activity. A further investigation into the mechanisms
of wound/burn healing bypanchvalkal 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 pharmacology

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.