Reverse

Pharmacology
DR. SIDDHARTHA DUTTA
MAMC, NEW DELHI
 History
• Sir Ram Nath Chopra was a pioneer in the field of
experimental pharmacology of indigenous drugs
of India

• Sir Ram Nath Chopra and Gananath Sen laid the foundation of
Reverse Pharmacology of medicinal plants by pursuing clinically
documented effects of Ayurvedic drugs

• Sen and Kartik Bose in 1931 demonstrated the

antihypertensive and tranquilizing effect of Rawolfia serpentina
• Unique side effects such as depression, EPS, Gynecomastia and
peptic ulcer
 Key words
Hit:
• A compound which has the desired activity/ robust dose
response activity in a compound screen and known,
confirmed structure whose activity is confirmed upon
retesting
Lead:
• A representative of a compound series with sufficient
potential (measured by potency, selectivity, pk,
physicochemical properties, absence of toxicity and
novelty) to progress to a full drug development
programme.
• Increased activity at a chosen target (potency)
• Reduced activity against unrelated target (specificity)
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
• Understand the mechanisms of action at multiple levels
of biological organization

• To optimize safety, efficacy and acceptability of the

leads in natural products, based on relevant science.
Concept of Reverse Pharmacology
• ‘Laboratory to clinic’ progress of discovery pipeline to
‘clinics to laboratories’

• Conventional NCE Path

Molecule  Mice  Man

• Reverse Pharmacology Path

Man  Mice  Molecule  Man

• ‘Safety’ remains the most important starting point and

the efficacy becomes a matter of validation.
Rev Pharmacology- The need of the hour..
• Resistance
• Urgent to find new hits & lead compounds
• Most affected populations have little access to
western medicine
• Use of herbal medicines is the first line treatment in
rural areas.
Phases of Reverse Pharmacology
1) Experiential phase
• Includes robust documentation of clinical observations of the
biodynamic effects of standardized traditional 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 pre-
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 drug safety and efficacy
 Drugs obtained by RP
Ayurvedic Plant Evidence Spin-offs
Rauwolfia serpentine Anti-hypertensive Anti-depressants, L-dopa

Psoralea caryllifotia Anti-vitiligo PUVA-therapy

Berberis aristata Anti-infective Septic shock, anti-malarial

Picrorrhiza kurroa Anti-jaundice Hydrocholeretic, Anti-asthma

Commiphora wightii Anti-arthritic Hypolipidemic, FXR
Tinospora cordifolia Anti-pyrexial Anti-cancer, Immune enhancer

Curcuma longa Anti-inflammatory Cancer-preventive, NFKB

Azadirachta indica Dermatological Anti-cancer, anti-malarial

Terminalia chebula Laxative CCK-receptor, memory

Phyllanthus emblica Anti-ageing Free radical scavenger

Drug discovery: Current scenario
• Discovery of blockbuster drugs-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
• The number of approvals for new drugs has steadily declined
• R&D expenses have risen from $2 billion in 1980 to over $50
billion in 2014
 Current scenario
• Drug discovery and development process involves a 10-15
years of investigation period and investments of of US $ 1 to
1.5 billion

• The pharmaceutical companies are looking beyond

conventional drug discovery

• Natural product drug discovery, ethnopharmacology,

traditional, complementary and alternative medicines are re-
emerging as new strategic options

• The WHO 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
Reverse Pharmacology: India
• Currently, CSIR through the New Millennium Indian Technology
Leadership Initiative(NMITLI) has adopted the path of RP

• The NMITLI team in the last 4 yrs has networked for R&D in a
multi-institutional, multi-disciplinary endeavor in diabetes,
arthritis and hepatitis

• ICMR has established an Advanced Centre for Reverse

Pharmacology where the research focus is on diabetes,
musculo-skeletal health, malaria, cancer and neurological
disorders
• A multidisciplinary and multi-institutional team involving TIFR,
KEM Hospital, C U Shah College of Pharmacy, Drexel University
School of Medicine
 Guggulipid
• Composite drug research program jointly conducted
by ICMR and CSIR of GOI

• Guggulipid was developed from

Commiphora mukul
taking the lead from Ayurveda

• DCGI approved the drug for marketing in 1986

• Guggulipid is being manufactured and marketed by Cipla, Guglip

• A memory enhancer developed from Bacopa monnieri by CDRI,

Lucknow is also available in market
Nyctanthes arbor-
tristis Linn
• Antimalarial activity

• Plant extracts shown anti plasmodial effects in vitro and

disease modifying activity in patients

• ICMR- Advanced Centre of Reverse Pharmacology in

Traditional Medicine, in collaboration with the Centre of
Molecular Parasitology at the Drexel University College of
Medicine
Case studies
• Artemisinin—
• Herb Artemisia annua has been used for many centuries in
Traditional Chinese Medicine as a treatment for fever and
malaria

• In 1971, Artemisinin from the leafy portions of the plant

• Artimisinin and its derivatives offer promise as a totally

new class of antimalarials

• Best case for reverse pharmacology approach

• Anti-cancer, asthma and anti oxidant properties

Psoriasis
• Under NMITLI project, Lupin Laboratories(India)
attempted development of a single plant based
oral herbal formulation through RP

• The drug candidate (Desoris) is an herbal beneficiated extract

of leaves of Argemone mexicana

• Novel mechanism of action and effectively modulates the

cellular function leading to psoriatic lesion improvement
 Psoriasis
• Extensive studies comprising toxicology, efficacy, safety, PK, PD
helped the company filing an IND application

• Lupin completed the Phase I clinical trial in September 2004 and

phase II in 2005

• This drug has been developed conforming to the US FDA

guidelines for botanicals and DCGI norms on new drug
development

• Expectations- 5-6 years and cost US $ 5 million as against

routine 10-15 years and US $ 1-1.5 billion

• Cost US $ 50, quite a step down from a new US $ 20,000

antibody injection
 Parkinson’ s disease
• Mucuna pruriens seeds for the treatment of PD

• 3.1–6.1% L-DOPA with trace amounts of

serotonin & nicotine

• Anti-venom, Libido and Fertility,

Neuroprotection

• Collaboration between Academia and Zandu Pharmaceutical

Works(Mumbai)

• Their team conducted series of experiments on Mucuna to

develop a natural drug for Parkinson’s disease
 Parkinson’ s disease
• The US FDA approved New Drug Application for clinical
studies
• L-dopa vs Macuna
• Mucuna Pruriens was noted less dyskinesia
• Hypothesized to have unknown Dopamine Decarboxylase
inhibitor

• Zandopa is now approved by the Indian FDA

• This standardized, safe and economical natural product

can effectively replace synthetic L-DOPA formulation
 Osteoarthritis
• 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 & the assay battery

involved targets relevant to inflammation, pain,
immunomodulation and chondroprotection in a model of OA
cartilage damage
 Osteoarthritis
• Short listed formulations entered series of RCT with
glucosamine and celecoxib

• This project was completed in 5 yrs 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
Re-discovery of the paradigm of reverse pharmacology

Medicinal Plant Clinical Effect Experimental Correlate

Curare tomentosun Paralysis and death Neuromuscular block

Papaverum Analgesia Opioid receptors

somniferum

Physostigma Ordeal poison Anticholinestrease

venenosum

Cinchona Fever cure Antimalarial

Digitalis purpurea Dropsy Na+ - K+ ATPase

Salix alba Fever and pain relief Prostaglandins

 Hurdles
• Despite a vast potential and possibilities --very few success
stories

• Most of the work in this field has remained within clinics of

traditional practitioners or confined to academic research
laboratories

• Improper experiential documentation

• Lack of proper identity and implementation of Good Laboratory
Practices
• Absence of Phase II dose optimizing studies
• Cultural prejudice for alien science
• Lack of political and financial support
 Future Perspectives
• Awareness 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

• NMITLI has resulted in hits, leads and effective formulations for

diabetes, arthritis and hepatitis with novel mechanism of
action and intellectual property

• India has amended the Drug Act to include a category of

phytopharmaceuticals to be developed from medicinal plants
by RP, with evidence of quality, safety and efficacy

• India and its pluralistic health care system

 Conclusion
• Traditional knowledge and experiential database can provide
new functional leads to reduce time, money and toxicity – 3
main hurdles in the drug development

• Need of the time- To document unknown, unintended and

desirable novel prophylactic and therapeutic effects in
observational therapeutics

• These records are particularly valuable since effectively these

medicines have been tested for thousands years on people

• 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
Thank You