Reverse pharmacology scope in India
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concise presentation on reverse pharmacology. Its history,scope, domains, phases, discoveries,examples, hurdles, future prospects,
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Reverse pharmacology scope in India
- 1. Reverse Pharmacology DR. SIDDHARTHA DUTTA MAMC, NEW DELHI
- 2. 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
- 3. 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)
- 4. 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.
- 5. 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.
- 6. 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.
- 8. 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.
- 9. 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
- 10. 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
- 11. 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
- 12. 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
- 13. 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
- 14. 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
- 15. 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
- 16. 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
- 17. 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
- 18. 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
- 19. 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
- 20. 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
- 21. 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
- 22. 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
- 23. 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
- 24. 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
- 25. 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
- 26. 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
- 27. Thank You
Notes de l'éditeur
- credit for stimulating interest of Indian chemists and pharmacologists in medicinal plants should go to Sir Ram Nath Chopra who has been acclaimed as the ‘Father of Indian Pharmacology”. As a spin-off of the side effects of Rauwolfia, several new drugs were developed L-dopa, antidepressants, bromoergocriptine, and H2-receptorblockers It took decades to delineate mechanisms of these side effects. This was a watershed for new antidepressants, anti Parkinson’s drugs and prolactin-reducing drugs
- Drug Target: Cellular/ molecular structures involved in the patho-physiology of interest where drug –in-development is meant to act on The output of a compound screen is typically termed a hit molecule, which has been demonstrated to have specific activity at the target protein lead--SAR established, Selectivity measured,● Mechanism of activity(reversible/irreversible,kinetics) established ● Preliminary PK in vivo(rodent) to establishbenchmark for in vitro SAR ● In vitro PK data go
- The traditional knowledge inspired reverse pharmacology relates to reversing the routine Faster, economical and safe Instead of serendipitous findings pursued randomly an organized path from clinical observations and success is established
- (RP), designed as an academic discipline to reduce three major bottlenecks of costs, time and toxicity
- Alternative medicine to combat those diseseases and therefore turn towards the use of traditional medicinal plants for their primary health care (WHO,2013) As most of the population get cured by the traditional medicine so it is quite obvious that the TM does work. So better to go for the established TM system and extract the new drug molecule rather than going for conventional drug discovery Reverse pharmacology offers a major paradigm shift in drug discovery
- Involving or based on experience and observation Documentation of clinical observations - toxicity report - efficacy Retrospective treatment outcome study (RTO) - clinical information - statistical analysis
- There are growing incidences where the old molecules are finding new applications through better understanding of traditional knowledge and clinical observations. For instance: Central Drug research Institute which were shelved for a considerable time are which may help in preventing conditions including obesity and atherosclerosis
- Hydrocholeretics are substances that increase the volume of secretion of bile from the liver without increasing the amount of solids secreted.
- The pharmaceutical industry has historically seen an incredible growth primarily due to the discovery of blockbuster drugs with the potential to generate over 1 billion US $ sales. The industry is really facing a major challenge to sustain and grow, which is resulting in many mergers, acquisitions or closures. However, recent trends indicate that this model may no longer lead to high growth rates. Clearly, drug discovery is no more a game of chance or just limited to technology availability today. The strategies that awarded success during the past ma y not guarantee success in the future Surprisingly, these increases have not led to a corresponding increase in the number and efficacy of new drugs.
- The pharmaceutical companies are looking beyond conventional drug discovery and development approaches not only to expedite the process, but also to ensure that safer and effective drugs could be launched faster and sustained It is the need of the time to document unknown, unintended and desirable novel prophylactic and therapeutic effects in observational therapeutics.
- 2--CSIR, under national network project known as NMITLI attempted to bring industry and academia together right from the beginning where herbal drug development projects on psoriasis, osteoarthritis, hepatitis and diabetes were undertaken at Bhavan's Swami Prakashananda Ayurveda Research Centre The results have been remarkable as to the hits and leads obtained. 3,, Most of these compounds are part of routinely used traditional medicines and hence their tolerance and safety is assumed to be better than any other chemical entities that are totally new for human use.
- Antarkar, Satyavati, and Nityanand have extensively studied on the hypolipidemic effect of guggulu Some promising work was undertaken almost 2-3 de however availability of authentic raw material has remained a limiting factor cades ago throughby Indian Council of Medical Research Council for Scientific and Industrial Research
- Parijat study inare being standardized and studied phytochemically as exploratory studies have already 120 patients, ninety-two (76.7%) showed complete parasite eradication and clinical cure within 7 days of treatment with the leaf paste of N. arbor-tristis This work has now been taken up by the ICMR
- Which\were lowered by Cyclophosphamide administration which is important for chemoprevention from alkylating agents induced O6 alkyl guananidines consisting of equimolar concentrations of sitoindosides VIIX and withaferin A evaluated for protection in iron induced hepatoxicity in rats.10 days of oral administration of these active principles, in graded doses (10, 20 and 50 mg/kg), resulted in attenuation of hepatic lipid peroxidation (LPO), the serum enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase during iron-induced hepatoxicity
- sweet wormwood, sweet anni Tu Youyou, for which she shared the 2015 Nobel Prize in Physiology or Medicine. Chinese chemists isolated active substance - responsible for its reputed medicinal action The efficacy of tea made from A. annua in the treatment of malaria is dubious. This discovery of Artimisinin for malaria is a result of scientific work based knowledge from and presents
- One of the common dermatological diseases with no preventive or curative therapy except the symptomatic management
- 11 Dec 2013 Lupin completes a phase II/III trial in Plaque psoriasis in India 18 Jun 2015 No recent reports on development identified - Phase-II/III for Plaque psoriasis in India (PO)
- Ayurvedic physicians in ancient India first used These observations inspired scientists to further study and led to
- reports of psychosis associated with Mucuna Pruriens ingestion (bean form), in which 203 cases of acute psychosis were recorded over a 6 week period during famine in Mozambique eating raw beans prior to sufficient preparation, and the results may have been a combination of protein deficiency paired with Levodopa, Bufotenin and N,N-dimethyltryptamine
- For osteoarthritis herbal drug development (proteoglycan release, nitric oxide release, aggrecan release and hyaluronidase inhibition as markers cells maintained in normal extracellular matrix This led to design of synergistic poly herbal formulations that were found to be safe and devoid of any genotoxicity or mutagenic activity
- Best formulation was selected that led to one Indian and one Patent Cooperation Treaty applications with a dossier of necessary data required for possible regulatory submissions.
- Strychnos nux-vomica Stimulant and convulsant Glycinergic receptors
- The drawback was that the long time lag from the observational therapeutics to a new drug. 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. 3--Used for ages but lack of doc—makes it mediocre from evidence based med 6..botanical medications continued to be produced in every country, their clinical efficacy was usually not evaluated and the composition of these complex mixtures was only crudely analyzed. Investments in these methodologies remained scarce. Failure to distinguish folklore from traditionally established systems 7--Majority of the drug discoveries would not have been developed or their development would have been delayed significantly in the absence of the scientific or technical contributions from the pharmaceutical companies
- Many countries are becoming increasingly aware New millennium Indian Technological Leadership Initiative These drugs will be distinct from traditional medicines 5….offers immense opportunities for natural product drug discovery and development based on traditional knowledge and clinical observations Linkages must be established with Observational Therapeutics and Ayurvedic Pharmacoepidemiology to identify clinical hits need to develop an academic niche for Reverse Pharmacology in medical and pharmaceutical sciences colleges and drug R & D centers.
- academic niche for Reverse Pharmacology in medical and pharmaceutical sciences colleges and drug R & D centers. Linkages must be established with Observational Therapeutics and TM to identify clinical hits Innovative approaches inspired by traditional knowledge will remain important to fast forward the discovery process and add new life especially in the existing global economic environment interest of pharmaceutical companies, researchers and ultimately the global community to respect the traditions and build on their knowledge and experiential wisdom Thus, if safe and effective herbal formulations are developed in accordance with stringent regulatory requirements on par with any modern drug, it is hoped that the conventional skepticism against herbals may slowly wane. With Ayurveda- a true Reverse Pharmacology Approach