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  1. 1. 115 29. INITIATIVES OF INDIAN COUNCIL OF MEDICAL RESEARCH IN SCIENTIFIC VALIDATION OF TRADITIONAL MEDICINE Nandini K, Kumar, Vasantha Muthuswamy, N.K. Ganguly The ‘Science of life’ as reflected in the wisdom and experience of ancient physicians has globally rekindled curiosity of man searching for an answer in Traditional Systems of Medicine to quell the emerging dissatisfaction with prevalent treatment modalities of Modern Medicine for chronic or refractory diseases. This interest had found an echo in ICMR’s research initiatives on indigenous drugs right from the Council’s very inception as is evident from the significant support given by the Council to the pioneering work of the late Sir Ram Nath Chopra, the Father of Indian Pharmacology, in the formative years of his career in India. Much later, through Ministry of Health, ICMR in collaboration with then Central Council ofAyurvedic Research and Central Scientific and Industrial Research (CSIR) had the privilege of conceiving, designing and technically implementing the unique Composite Drug Research Scheme (CDRS) during 1964-1970.1 During this period nine ‘circuits’ were set up in different parts of the country, each comprising four units.2 An advisory committee on indigenous drugs constituted in 1963 for this Scheme, brought together for the first time experts in the Ayurvedic System of Medicine and Modern Medicine (pharmacologists and clinicians) and scientists (botanists and phytochemists) for selecting and screening reputed Indian Medicinal plants for biological activity on the basis of their therapeutic claims. First batch of 58 medicinal plants was screened and nearly eight of these reached an advanced stage of investigation. In 1970, the Government of India transferred this unique Scheme to the then newly constituted Central Council for Research in Indian Medicine and Homoepathy (CCRIMH). Subsequently, with the branching of the CCRIMH into several independent Councils, such as Central Council for Research in Ayurveda and Siddha (CCRAS), Central Council for Research in Unani Medicine (CCRUM), Central Council for Research in Homoepathy (CCRH) and Central Council for Research in Yoga and Naturopathy (CCRYN), the Council never lost its basic interest in the scientific evaluation of these time-honoured ancient systems of medicine. Irrespective of the transfer of the CDRS in 1970, the Council continued research on indigenous drugs by promoting open- ended research in traditional medicine through ad- hoc research schemes and fellowships. One such scheme which had evoked keen interest was the ICMR/WHO project on the efficacy of Ayurvedic treatment for Rheumotoid arthritis at Coimbatore first and then as another sub-unit of the same project at Chennai in 1982. One year later the interim analysis of data collected on the revised protocol designed by a sub-Committee of Rheumatologists showed that the Ayurvedic line of treatment (as practiced by the TRM experts at Coimbatore) had analgesic/anti-inflammatory activity similar to the first line of modern anti- rheumatic drugs like the salicylate group of drugs did not possess any disease-remitting activity. In the wake of the renewed global interest in the Traditional Systems of Medicine and China re- discovering the well-known anti-malarial drug Qinghaosu from the common Artemesia plant marking an important milestone in global medicine in this direction, ICMR was inspired to strive for a similar breakthrough in Indian Medicine. Dr V Ramalingaswami, then Director General of the Council directed Dr. G.V. Satyavati to take up the task. Considering that the Pharmaceutical Industry in India, the foremost in the entire Third World, provides excellent facilities for generating quality products due to availability of high expertise in related specialized science to develop combinatorial chemistry, new synthetic molecules and plant derived candidate drugs, the efficacy of these new molecules may most often be proved futile. Therefore, the safer and cheaper alternative would be to simultaneously seek ways to 1 Research on Indian Medicinal Plants. In ICMR Bulletin vol. 2 No. 4, August, 1972. 2 Four Units comprised Clinical Unit of Ayurvedic and Modern Medicine physicians, Pharmacognosy Unit for botany, Chemistry Unit and Pharmacology Unit. Health Administrator Vol : XX Number 1&2 : 115-119Pg.
  2. 2. 116 standardize the already existent treatment modalities of traditional medicine. Keeping this in mind, the Council reconstituted its Advisory Group on Traditional Medicine comprising outstanding experts in Ayurveda, Siddha, Unani and Yoga systems on the one hand and experts in different branches of Modern Science / Medicine including pharmacolgists, phytochemists, botanists and clinicians on the other hand. Representatives of the CCRAS as well as CCRUM were also members of this Advisory Group. On the basis of the recommendations of the Scientific Advisory Board of the ICMR, Task Forces / Study Groups on some of the priority areas met in December, 1983 and January, 1984 to review certain time-honoured traditional therapies and also to provide valuable addition to the existing therapeutic armamentarium. The concept of reverse pharmacology was applied and the experts formulated time-bound goal- oriented projects on traditional remedies for Anal fistula; Diabetes mellitus, Viral hepatitis, Bronchial asthma, Urolithiasis, Filariasis, Kala-azar and Wound healing. For the seventh five year plan period, apart from the multicentric drug-oriented / disease oriented research, the vision of Traditional Medicine (TRM) programme was also to constitute Task Forces for preparation of compendium of traditional remedies / techniques on the basis of scientific evaluation for preparation of Monograph on Medicinal Plants of India, for cultivation of medicinal plants in collaboration with the ICAR, CSIR, National Botanical Survey etc and for synthesis / manufacture of selected plant products. Interaction with sister organizations like CCRAS, CCRUM, CCRYN etc. on the one hand, and the CSIR, ICAR, on the other were also on the cards. The Council also proposed to work out fruitful research schemes in collaboration with the unique “Ancient Insights and Modern Discoveries” (AIMD) project of the Bharatiya Vidya Bhavan, Mumbai and also have beneficial collaborative projects with international organizations like the WHO, UNICEF and others. But due to constraints of funds and infrastrudture only multicentric trials in six thrust areas viz. Anal fistula, Diabetes mellitus, Viral hepatitis, Bronchial asthma, Urolithiasis and Filariasis and a pilot study on snake bite could be taken up. A Central Coordinating Unit was created at the ICMR Headquaters with essential manpower and other facilities for monitoring each aspect of this new diseases oriented activity including timely supply of authentic traditional drugs for trial purpose through a multicentric and multidisciplinany approach. This activity was ably supported by the Central Biostatistical Monitoring Unit of National Institute of Epidemiology (Institute of Research in Medical statistics then) which helped in designing the trial protocols, drug dispatch, monitoring and analysis of the data. Two Advanced Centres i) at Central Drug Research Institute, Lucknow on Pharmacological Evaluation of Selected Traditional Remedies and (ii) at Regional Research laboratory, Jammu (earlier at Punjab) for standardization, Quality Control and Formulations of selected Traditional remedies were set up to provide necessary inputs for experimental studies and formulations for human study subjects. In the 8th plan period the leads obtained in the first Phase were pursed and consolidated. Khaarasootra, a medicated thread used for Anal fistula was found to be a safe, ambulatory and cost- effective alternative to surgery.3 The Russians showed keen interest in adopting this method. Pharmacopoeial standards have been achieved and a Monograph was prepared as also video- coverage of its production and quality control. A major breakthrough was achieved with the hepatoprotective drug. Picrorrhiza kurroa at the Council’s Advanced Research Centre at CDRI, Lucknow. Two active principles kutkoside and picroside showed synergistic activities and the combination was named Picroliv, which later paved the way for a controversy over a similarly named but differently proportioned product of the same plant in USA. This compound has undergone successful Phase I and Phase II trial in India and is ready for Phase III trial. In Diabetes the plant drug, Vijaysar showed promising results consistently.4 The clinical leads obtained in the other three areas could not be pursued further for various reasons although experimental studies gave encouraging results including Kala-azar and would healing, the two areas not yet taken up clinically. Newer identified areas like Benign Hypertrophy of Prostate, HIV/ AIDS, ischaemic heart diseases, ageing, and Cancer also could not be taken up. An “Illustrated Manual of Commonly Used Indian Plant Drugs” was brought out as an ICMR-CSIR effort during this period. An Institute for Research in TRM was also
  3. 3. 117 3 Multicentric randomized controlled clinical trial of Kshaarasootra (Ayurvedic medicated thread) in the management of fistula-in-ano. Indian Journal of Medical Research (B) 94: 177-185, 1991. 4 Flexible dose open trial of Vijayasar in cases of newly-diagnosed non-insulin-dependent diabetes mellitus. Indian J. Med Res 108, July 1998, pp 24-29 5 Efficacy of Vijaysar (Pterocarpus marsupium) in the treatment of newly diagnosed patients with type 2 diabetes mellitus: A Flexible Dose Double-Blind Multicentre Randomized Controlled Trial”. ICMR Study Group. Diabetologia Croatica, 34- 1, 2005. proposed at Belgaum, Karnataka. The Advanced Research Centre at CDRI, Lucknow was set-up and another centre for Clinical Pharmacology in Traditional medicine was initiated at KEM Hospital, Mumbai. During the 9th plan all the strategies which were planned during the 7th plan were to be initiated after prioritizing thrust areas based on strength of available resources and infrastructure for validating a limited number of drugs. The area of viral diseases like Herpes Zoster, Polio, HIV/AIDS, Viral Hepatitis, and ischaemic heart diseases, ageing, cancer, identified earlier by the Council were to be taken up during this period. Multicentric clinical trials on Vijaysar (Pterocarpus marsupium) in newly diagnosed cases of Diabetes mellitus (including extended study) were initiated. 5 The encouraging results obtained from these trials led to another multicentric trial in two groups – uncontrolled diabetics on single hypoglycemic drugs and those who opted for it. Under the inter-agency programme a second centre was set up in Clinical Pharmacology for pharmacokinetics, bioavailability and herb-drug interaction studies at BYL Nair Hospital, Mumbai, and for Standardisation and Quality Control of Selected Herbal Remedies / Natural Products at National Institute of Pharmaceutical Education and Research, Chandigarh. In the 10th plan validation of traditional knowledge was proposed on Shakhotak (Streblus Asper) for Wucherarian and Bancroftian filariasis, Arjuna (Terminalia arjuna) for cardiovascular diseases, Varun (Crataeva nurvala) for Benign Hypertrophy of Prostate, and a co0mpound formulation for cancer. Other activities included finger printing of selected herbal preparations, agrotechnology of selected plants for various clinical trials – Picrorrhia kurroa and Pterocarpus marsupium, and technology transfer to Pharmaceutical industries of Kshaarasootra and Vijaysar. On account of the expected increase in demand for the plant drug from Vijaysar, steps were taken for a dialogue between related Government agencies agencies to conserve Vijaysar trees, prevent their misuse as timber and start their cultivation by using appropriate agro-technolgy.6 The proposed Centres for Advanced Research will be Centre for Advanced Research in Yoga at Swami Vivekananda Yoga Research Foundation, Bangalore and Centre for Advanced Research for Reverse Pharmacology in Traditional Medicine at Bhavan’s S.P.A.R.C, Mumbai. The Centre for Advanced Research at CDRI, Lucknow focussed on three traditional remedies, namely, Picrorhiza kurroa (root and rhizome) for hepatoprotective activity, Centella asiatica (whole plant) for wound healing and Terminalia chebula (fruit) for adaptogenic activity. Phase II multicentric clinical trial on Picroliv was carried out in Mumbai, Jaipur, Varanasi and Lucknow. Phase III double blind clinical trial using placebo is being carried out in patients of tuberculosis receiving multi drug therapy and alcoholic cirrhosis in Mumbai at Seth G.S. Medical College and T.N. Medical College. In pattern profiling of Picrolive, a total of 27 components were detected by HPLC, fourteen components of which were quantified, and seven wee structurally characterized based on MS/MS fragmentation and available literature. Experimental studies on Centella asiatica showed that both the plant extract and its marker (K008) are potent angiogenic with significant wound healing activity in normal and diabetic wounds. Further, the extract and its fractions also showed significant anti- amnesic activity. The shelf-life and accelerated stability studies of the alcoholic extract and asiaticoside indicated stability for more than 2 years. Terminalia chebula and its marker (K022) showed significant anti-stress activity in various stress models. Shelf-life and accelerated stability studies of alcoholic extract and K022 indicated that both are stable for more than two years.
  4. 4. 118 6 ICMR’s Annual Report 1999-2000. The Centre for Advanced Research in Clinical Pharmacology in Traditional Medicine at T.N. Medical College, Mumbai carried out studies on mechanism of action of Pterocarpus marsupium, clinical and experimental evaluation of ACTM001 in diarrheoa and ACTM 002 for wound healing. Pterocarpus marsupium showed protection against damage, increase in insulin secretion, reduction in MDA formation with Streptozotocin and increased angiogenesis but with no insulinomimetic activity at tested concentrations. There was dose dependent increase in PBMC proliferation in normal volunteers, and the same effect is being studied in diabetic patients. There was also dose dependent increase in polymorphonuclear phagocytosis and inhibition of TPA induced oxidative burst. Viability assays on rat insulinoma cells (RIN) cells showed no viability upto 10 mg/ml but an increase in cell numbers as compared to control at certain concentrations. ACTM 001, a combination of Cyperus rotundus, Zingiber officinale and syzigium cummini was tried in diarrhea which could have an impact on public health. Cyperus rotundus inhibited bacterial translocation, but with no antibacterial effects. Zingiber officinale inhibited bacterial translocation and also exerted antibacterial effects. The wound healing action of ACTM 002, a “Classical” formulation used for would healing was validated. Ayurvedic parameters to assess response to medication, effect in diabetic patients, rate of wound healing, and bioassay guided standardization with respect to active markers were carried out. Training Courses were held on use of research methodology in traditional system to increase expertise in protocol designing. The Regional Medical Research Centre at Belgaum for traditional medicine research was conceptualized in 1983, and land was allotted in 1984 and finally initiated during this plan period. This centre will address the regional health problems in the state of Karnataka and also establish a National Centre to promote collaborative research between practitioners of Modern Medicine and Traditional system of medicine. The mission is to provide cost- effective quality healthcare through the traditional systems of Medicine. The mandate is to scientifically validate the claims of Traditional Medicine to provide evidence for global acceptance and to set up a Centre of excellence in Traditional Medicine research where human capacity will be developed and strengthened. The aims of this Centre will be validation of safety and therapeutic efficacy, study mechanism of action of herbal remedies and conduct clinical trials besides collection and dissemination of information on medicinal plants of Western Ghats and their cultivation / conservation. Survey on usage, availability and utility of TRM / Formulations in Belgaum region and evaluation of plants used in Ayurveda / Siddha for anti-oxidant activity and a cross-sectional study on the status of Reproductive and Child Health and Practice of Traditional Medicine in Belgaum District are other activities contemplated. Already a database has been created for medicinal plants of the Western Ghats. It is also proposed to undertake studies on pharmacoepidemiology and phytochemistry, set up a Museum for the medicinal plants of the Western Ghats and undertake cultivation of some of them. The Council has also brought out two volumes of “Quality Standards of Indian Medicinal Plants and four volumes of “Reviews on Indian medicinal Plants”. Further areas to be explored would include Adverse Drug Reactions due to herbal drugs, Natraceuticals (Herbal Health Foods) and genetically modified foods, IPR issues / Indigenous knowledge, Academia-Industry collaboration. The expanded network would involve Department of AYUSH (earlier ISM & H) for Clinical trials, preparation of Pharmacopoeia and quality drugs, DBT for bioconservation and Gene Banks, CSIR for Standardisation, quality Control and formulations, ICAR for agrotechnology and Department of Chemicals/Fertilisers for database and export of plant drugs. The objectives of this network would be to generate trained manpower, identify/ strengthen clinical trial centres, and referral centres for crude drugs, and conduct regular training programmes for trial designing and related ethics. The Golden Triangle partnership under a tripartite Agreement, is among the Department of AYUSH, CSIR and ICMR to develop formulations / plant based drugs for identified diseases. While the Department of AUSH will give technical guidance regarding formulations to be used, CSIR will carry out the pre-clinical studies on these
  5. 5. 119 formulations and ICMR will conduct the clinical trials. The objectives of the program are given below: 1. To develop safe and effective standardized Ayurvedic products for the identified disease conditions. 2. To develop new Ayurvedic and plant based products effective in disease conditions of national / global importance. 3. To develop mechanism to make products affordable in the domestic market. 4. To use appropriate technologies for development of single and polyherbal products to make it globally acceptable. 5. To develop potential patentable products. The fourteen areas of priority under this partnership will be Rasayana, Joint disorders, Memory disorders, Menopausal syndrome, Bronchial allergy, Fertility and infertility, Cardiac disorders (cardioprotective & anti-atherosclerosis), Sleep disorders, Irritable Bowel Syndrome, Vison disorders, Urolithiasis and Benign Prostate Hypertrophy (BPH), Malaria / Filaria / Leishmaniasis, Diabetes and Bhasma toxicity. With regard to regulation of the plant drugs ICMR has brought out ethical guidelines which would soon be legislated through a bill for Promotion and Regulation of Biomedical Research. The recognized Indian Systems of Medicine are Ayurveda, Siddha and Unani, which use herbs and minerals in the formulations. Many of the drugs used in Modern Medicine also have been derived from medicinal plants but are marketed only after such drugs have undergone safety and efficacy evaluation in animals and human subjects in that order as per regulatory requirements. Since the traditional formulations used in the traditional way for traditional use are time tested, their safety and efficacy for validation could be straightaway evaluated through human trials provided, there are no reports of toxicity and the use is for not more than three months. If large Phase III clinical trials have to be undertaken then limited toxicity studies for 4 – 6 weeks in 2 species of animals should be undertaken. This concept of ward to lab strategy known as reverse pharmacology, was incorporated in the ethical guidelines for clinical trials using herbal medicines. The Drugs Controller General of India has accepted these guidelines, which are now incorporated in the Drugs & Cosmetics Act amendment of 2002. With this vision in mind the Council wishes to restore the glory to the Traditional Medical heritage of the country and utilize the revitalized knowledge to improve the health of the suffering millions of the country through a joint scientific effort.