Reverse pharmacology is an approach that begins with documented clinical effects of natural products and then uses experimental and clinical research to develop drug candidates from these effects. It involves three stages - experiential, exploratory, and experimental. The experiential stage involves documenting clinical observations of natural products. The exploratory stage involves dose-activity studies and in vitro/in vivo models to evaluate key targets. The experimental stage further studies plants or molecules at different biological levels to define safety, efficacy, and therapeutic potential. This approach has successfully rediscovered drugs in the past but was applied sporadically. Current research is now applying this approach in a multidisciplinary manner to develop drugs for conditions like diabetes, arthritis, and hepatitis.

1. REVERSE
PHARMACOLOGY
BY -DR. KAVITA TIWARI

2. INTRODUCTION
Reverse pharmacology is the science of integrating
documented clinical/experimental hits, into leads by
transdisciplinary exploratory studies
and further developing these into drug candidates by
experimental and
clinical research.

3. The scope of reverse pharmacology is to understand the mechanism 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. Reverse pharmacology comprises of
three stages—experiential, exploratory and experimental. Possessed with a pluralistic
healthcare, India offers a goldmine for robust experiential documentation of clinical
observations of bio-dynamic effects of standardised ayush or modern drugs.
SCOPE

4. The exploratory studies would cover dose-activity in ambulant patients and selected in-vitro and in-vivo
models to evaluate the key traget. These exploratory leads are evaluated critically for resource allocation and
state-of-the-art experimental studies like platelet aggregation with aspirin vis-à-vis bleeding and the role of
dopamine depletion in ex
trapyramidal disorders vis-a-vis Rauwolfia. The experimental stage involving relevant basic and clinical
science would be employed to study the plant or a molecule at different levels of biological organisation.
This would define the safety, efficacy, preventive or therapeutic dimensions of the new or natural drug . Fig.
—Drug discovery and development: Conventional versus reverse pharmacology

5. Fig. —Drug discovery and development: Conventional versus reverse
pharmacology.
(a)Conventional: Time, investment and risk intensive
(b) Traditional medicine inspired reverse pharmacology: Faster,
economical and safe

6. Medicinalplant Clinicalefffect Experimentalcorrelate
Curare tomentosum Paralysis and death Neuromuscular block
Papaverum somniferum analgesia Opioid receptors
Physostigma venenosum Ordeal poison anticholinesterase
Cinchona officinalis antipyrexia antimalarial
Digitalis purpurea Dropsy relief Na+,K+-ATPase
Salix alba Fever and pain Prostaglandins
Strychnos nuxvomica CNS stimulant Glycinergic receptors
Table 1
Rediscovery of the paradigm of reverse pharmacology

7. IN PRACTICE
The reverse approach in pharmacology has been quite successfully applied in the past. The drawback was
that the long time lag from the observational therapeutics to a new drug. For example, Raulwolfia
serpentina was convincingly demonstrated to be an anti-hypertensive by Gananath Sen and Kartik Bose in
1931. But a drug reserpine, emerged only after 20 years of work by Vakil, Bein, Mueller and Schlittler.
This happened because the path of reverse pharmacology was random and quite discontinuous.
Currently, CSIR through the New Millennium Indian Leadership Initiative (NMITLI) has adopted the path
of reverse pharmacology. The NMITLI team in the last four years has networked for R&D in a multi-
institutional, multi-disciplinary endeavour in diabetes, arthritis and hepatitis.

8. Advantages to ayurveda :
 dynamic substances of animal, plant and mineral origin. Ayurveda has the term Veda, which
implies revealed or inspired knowledge, often taken as too sacred to be challenged or
investigated. Lokmanya Ayurveda, currently under attack for heavy-metal usage or
contamination, has a rich heritage of bio-Tilak coined the term 'ayurvidya' to liberate the
creative and research potential of our inherited health wisdom. There has been a renaissance
in ayurvedic research that the western and Indian pharma companies have just started to
notice. Table-2 lists the plants and drugs of Ayurveda with an evidence of safety and efficacy.

9. The results have been remarkable as to the hits and leads obtained. The paradigm
of reverse pharmacology is actually a rediscovery of the path, which founded
modern pharmacology. Table 1 lists the names of plants, clinical effects and
experimental correlates. This list illustrates how novel clinical bio-dynamic effects
can lead to the development of the basic disciplines in pharmacology and biology.

10. Reverse pharmacology was only sporadically applied to new drug development. It is the need of the time to
document unknown, unintended and desirable novel prophylactic and therapeutic effects in observational
therapeutics. Several new classes of drugs have accidentally emerged by this path. For example, oral
sulphonylureas emerged due to hypoglycaemicreactions to certain sulphonamides Thalidomide optical isomer
emerged to be useful to control erythema nodoium and for multiple myceloma. Bromocriptine was first shown
clinically in India to regress pituitary prolactinoma. Then, the new micro-prolactoma therapy emerged.
Recently, an excellent review was written by Takeshi Sakurai on reverse pharmacology of orexin. He traced the
two orphan G- protein coupled receptors (GPCRs) which were orphans until orexins were shown as the
endogenous ligands for the regulation of energy homeostasis. The GPCRs as targets orexin knockout mice and
small molecular mimics of orexins have mushroomed as a major field for the new anti-obesity drug
development.

11.  Recently, ICMR has established an advanced Centre for Reverse Pharmacology
at Bhavan's Swami Prakashananda Ayurveda Research Centre, where the
research focus is on diabetes, musculo-skeletal health, malaria, cancer and
neuronal plasticity. A multidisciplinary and multi-institutional team involving
TIFR, KEM Hospital, C U Shah College of Pharmacy, Drexel University School
of Medicine, PERD of target disorders.

12. Reverse pharmacology examples :-
 1. Macuna pruriens for Pakinson’s disease
 2. Zingiber officinale for nausea/vomiting
 3. Picrorhiza kuroa for hepatitis
 4. Curcuma longa for Oral cancer
 5. Panchvalkal for burns and wounds
 6. Azadirachta indica for Malaria

13. Table 2: Ayurvedic plants with evidence
 Ayurvedic Plant Evidence Spin-offs
 Rauwolfia serpentine Anti-hypertensive Anti-depressants, L-dopa
 Psoralea caryllifotia Anti-vitiligo PUVA-therapy, diabetes
 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


14. Thank you