Consultation and Interaction at CSIR New Delhi with WHO-CIPIH Traditional Approach

Bhushan Patwardhan, PhD Interdisciplinary School of Health Sciences University of Pune India Innovation Deficit

• Just 26 NCEs in 2003 • Average innovation deficit: 1.3 NCE/ year • Increased Development time • Safety and remain challenging • Failure at the end of pipeline • Substantially increased development costs Bioprospecting challenge

• Symptomatic therapeutics now aims at cause of disease. • Earlier therapeutics: indirect, conjectural and coincidental, is now, direct and definitive based on intent. • Combichem of Nature • Major Discovery Engines are based on knowledge of little traditions. • Great traditions are the true resources Discovery Approaches

• Ethnopharmacology Approach • Serendipity and Synthetic Approach • Chemical Biology Approach • Genomics Approach • Reverse Approach • Systems Biology Approach • Personalized Approach , Reverse Pharmacology and Ayurveda

Field use Ayurvedic usage

Experimental documentation Whole formulations Standardize (Observation)

Ethnomedicines AYURVEDIC Exploratory studies THERAPEUTICS

Medicinal Plants Experimental Research Standard extract Screening of extracts Clinical Phase II Clinical trial Isolation of active principles

Therapeutics Herbal medicine Modern drug Reverse Pharmacology: From Clinic to Laboratory • Clinical wisdom • Disease focus • National Consultations • Pharmaceutics • Team India • Pre-clinical • Pharmacoepidemiology • Protocol development • Bioprospecting • Stage I RCT • Quality control methods • Data consolidation • Chemoprofile • Phase II and Phase III • Herboprint • NMITLI Herbal Drug Development 3 Years Outcome • Rheumatic and Musculoskeletal Disorders – Osteoarthritis, Rheumatoid arthritis – Stage I RCT indicated one formulation significantly better than Glucosamine • Hepatic Disorders – Pre-clinical suggest better activity than sylimarine • Diabetes – Pre-clinical suggest better insulin sensitizing activity Leads from Ayurveda

Curcumin, Gingerol, Gugullosterones, Eugenol, catechins, Anethol, Piperine, Apocynin, Genestein, polysaccaharides from TC, biflavanoids from Semecarpus, Gallates, Bacosides, Boswellic acid, Glycrrhizin, Allicin... Curcuma longa

• Ayurvedic description • Lead molecule: Curcumin

• Biological targets: Aryl hydrocarbon , Cytochrome P450 enzymes, Glutathione S-transferase, kinases, COX, iNOS, MMP • Therapeutic class: Cancer, Inflammation, Diabetes and Chemo prevention Chen HW.Anti-invasive gene expression profile of curcumin in lung adenocarcinoma based on a high throughput microarray analysis. Mol Pharmacol. 2004 Jan; 65(1): 99-110. Limtrakul P, Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids.BMC Cancer. 2004 Apr 17; 4(1): 13. Zingiber officinale

• Ayurvedic description • Lead molecule: Gingerols

• Biological targets: Vannolloid receptors • Therapeutic class: Antipyretic, analgesic, antitussive, cardiotonic, and sedative

Dedov VN. Gingerols: a novel class of vanilloid receptor (VR1) . Br J Pharmacol. 2002 Nov; 137(6): 793-8. Ohizumi et al. Stimulation of sarcoplasmic reticulum Ca (2+)-ATPase by gingerol analogues. Biol Pharm Bull. 1996 Oct; 19(10): 1377-9. Multiple Targets Need A Combo Pain, Cartilage Bhallataka Inflammation Guggulu Oxidative stress Ginger Osteoporosis Ashwagandha Anabolic Nirgundi CNS Immunomodulato Guduchi Antistress Pipali Erand Lubricant Activity Matrix: Systems-Biology Approach Combinatorial, Holistic and Systems Approach: The Most Modern View • The preparation of dual- or multiple-ligands on an almost rational basis is now conceivable and it can be expected that many of these molecules will yield of superior clinical value compared with monotarget formulations.

Multitargeted drugs: The end of the ‘one-target-one- disease philosophy? Camille Wermuth, DDT 19, October 2004 Ayurveda: Systems Advantage

Standardized traditional formulations for in-house use

Science base Drug Discovery Multi-prone Approach Evidence to engine to understand reduce Target mechanisms to Lead bottleneck Chemical biology approach for new Leads Natural product extract libraries Holistic and Personalized Concepts Traditions and Modernity: Future Medical Science

Golden Triangle approach promotes effective integration of traditional wisdom, power of contemporary science & technology and the evidence base of modern medicine where the holistic strategies reflect from the systems biology principles. Golden Triangle approach provides holistic or whole person healing viewpoint besides a new platform for drug Mashelkar R.A., Chitrakoot discovery. Declaration, 2003 Thank You!

With Dr. Ashok Vaidya and the CSIR NMITLI Team Backup slides Arthritis:Commonly used plants

• Bhallataka: Pain, Multi-targets? •Erand:Cartilage? Lubricant • Guggulu: Inflammation • Ginger: Oxidative stress, Osteoporosis • Ashwagandha: Anabolic, Adaptogen, CNS • Nirgundi: Pain, Inflammation • Guduchi: Antistress • Pipali: Bioavailability AAA comprehensive,comprehensive,comprehensive, interactiveinteractiveinteractive andandand intelligentintelligentintelligentAyuSoftAyuSoftAyuSoft softwaresoftwaresoftware toto assistassist MedicalMedicalMedical PractitionersPractitionersPractitioners andandand ResearchersResearchersResearchers ininin ApplicationApplicationApplication ofofof BasicBasicBasic PrinciplesPrinciplesPrinciples ofofof AyurvedaAyurvedaAyurveda AyuSoftAyuSoftAyuSoft ::: DataDataData WarehouseWarehouseWarehouse

AyuSoft: Decision Support System Prakruti assessment, Disease Diagnostics, Diet & Lifestyle advice Encyclopedia

PIMS Knowledge Database

Drug Database

Diet, Lifestyle Database Treatment Principles

Disease Database

Shaarir : Dosha, Dhatu, Mala Classification of human population based on Ayurvedic concept of Prakruti : (n=76) Distribution of HLA alleles in Prakruti

HLA Distribution in Kapha Prakruti HLA Distribution in Pitta Prakruti HLA Distribution in Vata Prakruti DRB1 DRB1 DRB1 alleles alleles alleles 1 1 1 2 2 2 3 3 3 4 4 4 7 7 7 8 8 8 9 9 9 10 10 10 11 11 11 12 12 12 13 13 13 14 14 14 15 15 15 *11/13 *11/13 *11/13

Cold Spring Harbor November 2004: Drug Discovery and Development Process

Expensive, time consuming, numerous bottlenecks

TARGET LEAD LEAD PRECLINICAL CLINICAL IDENTIFICATION IDENTIFICATION OPTMIZATION STUDIES TRIALS

DRUG TO MARKET

Economical, time sparing, least bottlenecks Reverse Pharmacology

DRUG PRECLINICAL CLINICAL RELEVANT STUDIES TRIALS LARGE SCALE TRIALS DEVELOPMENT SCIENCE PHASE II & I DRUG TO MARKET Other Efforts

• CSIR-TKDL, NMITLI Efforts • Not just materials BUT the Systems – Traditional wisdom has a message, logic and capturing intelligence from traditional information is important knowledge that needs protection AyuSoft project of MICT

Thank you!