REVERSE PHARMACOLOGY&

DRUG DISCOVERY

ILHAR HASHIM, M PHARM-CLINICAL RESEARCH

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), MOHALI, INDIA-

160062

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 &

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

CONCEPT OF REVERSE PHARMACOLOGY

The traditional knowledge inspired reversepharmacology relates to reversing the routine‘laboratory to clinic’ progress of discoverypipeline to ‘clinics to laboratories’.

The ayurvedic knowledge database allowsdrug researchers to start from a well testedand safe botanical material.

Thus in ayurvedic medicine research, clinicalexperiences, observations or available databecomes a starting point.

In conventional drug research, it comes at theend.

CONCEPT OF REVERSE PHARMACOLOGY

Thus the drug discovery based on ayurvedafollows a ‘reverse pharmacology’ path.

Conventional drug discovery path

Molecule Mice Men

Reverse pharmacology path

Man Mice Molecule

In this process ‘safety’ remains the mostimportant starting point and the ‘efficacy’becomes a matter of validation.

CONCEPT OF REVERSE PHARMACOLOGY

CONCEPT OF REVERSE PHARMACOLOGY

Traditional medicine

Modern medicine Modern science

Reverse pharmacology is ‘Transdisciplinary’.

Efficient discovery engine

DRUG DISCOVERY:CURRENT SCENARIO

The incredible growth of pharmaceuticalcompanies due to the discovery of blockbusterdrugs is coming to an end.

The average cost and time of discovering,developing and launching a new drug isconsistently increasing without an expectedcorresponding increase in the number of newer,safer and better drugs.

New molecular entities produced per companyhave declined.

DRUG DISCOVERY:CURRENT SCENARIO

The strategies that awarded success during

the past may not guarantee the same in the

future.

So the industry is facing a major challenge to

sustain and grow, which is resulting in many

merges, acquisitions or closures.

PHASES OR DOMAINS OF REVERSE PHARMACOLOGY

PHASES OR DOMAINS OF REVERSE PHARMACOLOGY

So reverse pharmacology is transdisciplinaryaspect that is comprised of three phases ordomains.

1. Experiential

2. Exploratory

3. Experimental

EXPERIENTIAL :

This phase includes robust documentation

of clinical observations of the biodynamic

effects of standardized ayurvedic drugs by

meticulous record keeping.

EXPLORATORY :

This phase includes the studies for tolerability,

drug interactions, dose range finding in

ambulant patients of defined subsets of the

disease and paraclinical studies in relevant

invitro & invivo models to evaluate the target

activity.

EXPERIMENTAL :

In basic & clinical, at several levels of

biological organisation, to identify and

validate the reverse pharmacological

correlates of ayurvedic drug safety and

efficacy.

DRUGS FROM REVERSE PHARMACOLOGY PATH

ARTEMISININ

The artemisinin was developed from the herb

Artemisia annua that has been used for

many centuries in Chinese traditional

medicine as a treatment for fever and

malaria.

Now artimisinin and its derivatives offer a

promise as a totally new class of

antimalarials.

DESORIS

This drug candidate is a 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.

Lupin commenced the phase1 clinical trial in

september 2004 successfully completed it.

If successful, the resulting treatment with

Desoris only cost US $ 50, when compared

to new US $ 20,000 antibody injection

treatment.

Rauwolfia alkaloids for hypertension.

Psoralens in Vitiligo.

Holarrhena alkaloids in Amoebiasis.

Picrosides in hepatic protection etc…

REVERSE PHARMACOLOGY: HURDLES

Despite a vast potential and possibilities very

few success stories are available till now.

Most of the work in this field has remained

within clinics of traditional practitioners and

are not taken by industries that are strong in

research and development.

The pharmaceutical industry needs many

more successes like artemisinin & reserpine.

FUTURE PERSPECTIVES

Many countries are increasingly aware of the

value of their traditional knowledge.

Global pharmaceutical industry is looking for

innovative solutions to re-activate and re-

energize their discovery pipeline.

Therefore, innovative approaches inspired by

traditional knowledge will remain important to

fast forward the discovery process

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

those medicines have been effectively tested for

thousands of years on people .

With the reverse pharmacology approach, the

normal drug discovery course of ‘Laboratory to

clinics’ becomes from ‘Clinics to Laboratories’.

India with its pluralistic health care system offers

immense opportunities for natural product drug

discovery and development based on traditional

knowledge and clinical observations.

So reverse pharmacology approaches need to be

further developed and optimized as novel means

for fast track drug discovery and development of

newer, safer & effective drugs.

THANK YOU