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 wordsHit: • 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 PathMolecule Mice Man

• Reverse Pharmacology PathMan 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 Pharmacology1) 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-offsRauwolfia 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 somniferum

Analgesia Opioid receptors

Physostigma venenosum

Ordeal poison Anticholinestrease

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