Special Article

Reverse pharmacological correlates of ayurvedic actions*actions*

A.D.B. Vaidya

Bhavan’s Swami Prakashanand Ayurvedic Research Center (SPARC), Mumbai – 400 049. India

Received: 28.7.2005 Revised: 22.5.2006 Accepted: 30.5.2006

Correspondence to: Ashok DB Vaidya Sir Ram Nath Chopra E-mail: [email protected]

The human condition has been enhanced considerably by While Sir Ram Nath Chopra and other West-trained those biochemists and pharmacologists who have applied the scientists were evaluating the effects of ayurvedic and scientific method to prove ancient myths and legends. For plant extracts on tissues and animals, eminent vaidyas such example, the mystical powers of the snakeroot plant of India, as Mahamahopadhyaya Gananath Sen were laying the either ignored or ridiculed by scientists for decades, were foundation of ‘Reverse ’. The science of dispelled with the isolation and identification of its active integrating documented clinical/experiential hits into leads by transdisciplinary exploratory studies, reverse alkaloid. pharmacology further developed these leads into drug candidates by experimental and clinical research. The – Richard E Davis proposed approach is the new paradigm or a rediscovered paradigm. “Rediscovered” because, even in modern Sir Ram Nath Chopra (1882-1973) was a pioneer in the pharmacology, some of the major fundamental discoveries field of experimental pharmacology of indigenous drugs of evolved from plant effects in humans. Table 1 lists some India. Most of the medicinal plants he studied were in use, in such historical examples of reverse pharmacology. The animal ayurveda, for thousands of years. At the Calcutta School of models and/or mechanisms of such human effects often Tropical , he pioneered a paradigm, a pace and a provided the foundation of pharmacology. Novel phenomena pattern of research in studying the actions of medicinal plants, in healthy or ill humans still continue to occur and deserve a which influenced an entire generation of pharmacologists, critical study at different levels of biological organisation. This pharmacists and physiologists in India. Fortunately, now, at can be an engaging and challenging task. It is possible that the Regional Research Laboratory (RRL) Jammu-Tawi, the such a quest for biodynamic mechanisms can generate new Chopra Archives are safely lodged for posterity. The collected disciplines in life sciences. works, correspondence and materials may also serve as Ayurveda in India dates back to 3000 BC. It has a valuable sources for a biography which can be commissioned connotation of revealed knowledge, complete within itself and, by the Indian National Science Academy, which had the as some say, it has hardly any need for research. Lokmanya privilege of having Dr. R.N. Chopra as past president. Tilak coined the term ‘Ayurvidya’ to liberate the creative and G.V. Satyawati, former Director General, Indian Council of research energies of this great heritage of healing wisdom. Medical Research (ICMR) has rightly emphasised, “The credit India is a unique, democratic nation with a multi-population, for kindling the interest of Indian chemists and divergent lifestyles and pluralistic healthcare systems. Such pharmacologists in medicinal plants should rightfully go to diversity offers an immense scope to observe and document Sir Ram Nath Chopra, who has been acclaimed as the ‘Father the effects of ayurvedic drugs, medicinal plants, dietary habits of Indian Pharmacology’”.[1] and non-drug healing modalities. Reverse pharmacology

*Based on the ‘Sir Ram Nath Chopra’ oration delivered by the author at the Annual Conference of the Indian Pharmacological Society on 10th January 2002 in Nagpur.

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Table 1 the plant? It is worthwhile to apply combinatorial chemical methods for reserpine derivatives, which do not cross the Rediscovery of the paradigm of reverse pharmacology blood brain barrier, so that depression, a serious side effect, Medicinal Clinical Experimental is avoided. The uptake of norepinephrine by isolated plant effect correlate chromaffin granules, by inhibition of ATP-Mg2+ – dependent mechanism has to be studied afresh at the transcriptional Curare tomentosum Paralysis and death Neuromuscular level. Though reserpine is withdrawn globally, the extracts of [2] block the plant are still used in ayurveda with a rationale of Papaverum somniferum Analgesia Opioid receptors[3] ayurvedic . There is a need to conduct Physostigma venenosum Ordeal poison Anticholinesterase[4] pharmacovigilance on Sarpagandha ghanavati (water extract).

Cinchona officinalis Antipyrexia Antimalarial[5] Psoralea corylifolia Linn (Bakuchi) Digitalis purpurea Dropsy relief Na+,K+-ATPase[6] The use of this plant in treating leucoderma is well Salix alba Fever and pain relief Prostaglandins[7] documented in Rajnighantu (Nighantu – a compendium of synonyms, properties and usages of medicinal plants) by Strychnos nuxvomica CNS stimulant Glycinergic Pandit Narahari.[15] Besides the traditional and classical use of [8] receptors P. corylifolia in treating leucoderma (shwitra kusta), there are many other indications described in classic ayurveda texts such as Bhavaprakash Nighantu.[16] These indications include would initiate the research process from the robust clinical promoting skin health, hair growth, relieving attacks of base of documented therapeutic or other effects of plants asthma and bronchitis and reducing inflammatory and and formulations. edematous conditions. Though the pharmacological As an academic discipline, it comprises 3 phases: correlates of its pigment enhancing and antipsoriasis actions 1. Experiential robust documentation of clinical have been studied, the other ayurvedic actions too deserve observations of the biodynamic effects of standardised attention.[17] The phytochemically induced covalent binding ayurvedic drugs by meticulous record keeping. of methoxalen to pyrimidine bases is responsible for its 2. Exploratory studies for , drug interactions, dose therapeutic effect. The photoconjunction involves thymine range finding in ambulant patients of defined subsets of dimer adducts on the opposite strands of DNA. With the the disease and para-clinical studies in relevant in vitro current advances in human genomics, it would be worthwhile and in vivo models to evaluate the target activity. to investigate whether such effects on DNA are localised to 3. Experimental studies, basic and clinical, at several levels the skin only and whether hair, retina and so on are also of biological organisation, to identify and validate the affected. The other ingredients of the plant need to be studied, reverse pharmacological correlate of ayurvedic drug in the reverse pharmacology mode, for the effects on edema, safety and . asthma cough and anaemia. An overt focus on a single active Such a creative research endeavour requires an excellent principle leads to the neglect of other active entities in the teamwork by multisystem and multidisciplinary experts. plant. The external uses described in ayurveda deserve due Reverse pharmacology, for drug development, has been attention.[18] highly productive and cost effective in the recent past. Berberis aristata D C (Daruharidra) Globally, this approach has now generated greater interest in ayurveda and Indian pharmacology. The multiple uses and actions of the plant, Berberis aristata (Daruharidra), have always intrigued pharmacologists Rauwolfia serpentina Benth (Sarpagandha) and clinicians. It is a topical antimicrobial par excellence in Sen and Bose[9] not only showed the antihypertensive ayurveda. Its use, as extract for eye drops in conjunctivitis, is effects of R. serpentina, but were also astute clinicians to widespread. The active principle of the plant, berberine, has note certain side effects such as Parkinsonism, depression, been extensively studied. The activity of berberine against a gynecomastia, acid peptic symptoms and so on. There was variety of organisms, including bacteria, viruses, fungi, almost a gap of two decades in discovering the protozoa, helminths and chlamydia, has been pharmacological basis of these actions. The storage vesicles demonstrated.[19] Berberine has been shown to bind to DNA are rendered dysfunctional as a result of their interaction and inhibit its cleavage.[20] There is an urgent need to develop with reserpine and the depletion of biogenic amines explained specially targeted drug delivery systems of berberine, for the actions by mechanistic correlates.[10] As a spin off of the topical and systemic antimicrobial use. Local anesthetic, side effects of R. serpentina, several new drugs were developed pigment inducing, enzyme inhibitory, antihypertensive, such as L-dopa, antidepressants, bromo-ergocriptine, and antipruritic and antipyretic activities have been reported with [11-13] [21, 22] H 2 blockers and so on. The alkaloids of berberine. Recently, the antiamnesic activity of berberine R. serpentina, reserpine and ajmalcine, have served as has been reported.[23] Despite the diversity of activities, the research tools in many experiments.[14] proper clinical documentation of the reverse pharmacology However, there are still some unanswered questions. Does of the plant has been neglected. Its beneficial effects on reserpine have more incidence of depression and/or Plasmodium vivax relapses have been reported by Gogte.[18] extrapyramidal side effects than the standardised extract of But experiential documentation is urgently needed.

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Picrorrhiza kurroa Royle ex Benth (Kutki) surgery.[33] Recently, Chintalwar et al, have shown that the polysaccharide fraction of the plant has a mitogenic effect on Arogyawardhani (a herbo-mineral formulation) was the B-lymphocytes of the spleen.[34] popularizsd by the late vaidya, Zandu Bhattji, for the treatment Clinically, the water extract of T. cordifolia has been used of jaundice. A double blind trial with arogyawardhani, kutki to treat pyrexia of unknown origin, frequently, with gratifying and placebo was conducted in viral hepatitis. Significant results. The pharmacological correlates of the antipyretic hepatoprotective effects were observed with kutki, as a single actions at the molecular level[35] must be understood ayurveda plant or as an ingredient in arogyawardhini.[24, 25] Later, regards jwara (fever) as a disease entity and not merely as a picrosides, the active principles of kutki, were also tested symptom. Exploring the mechanisms of the jwaraghna in vivo and in vitro. Significant antioxidant as well as (antifever) property of these plants and products such as hydrocholeretic effects were noted for kutki. These effects of T. cordifolia gives us a totally different perspective on fevers. hepatoprotection in carbon tetrachloride (CCl ) and 4 The use of the plant, as a standardised formulation viz. galactosamine models are considered the pharmacological Immumod® (Wockhardt Pvt. Ltd.) 500 mg, b.i.d., before and correlates of clinical actions. However, there is a need to study, after cancer , has led to a reduction in the at the cellular and molecular levels, how the water outflow in incidence of nausea, vomiting and granulocytopenia. the biliary microcanaliculae is enhanced. The Central Drug However, there was no reduction in alopecia.[36] Research Institute (CDRI), Lucknow, has now developed a cucurbitacin-free extract of P. kurroa (Picroliv®) which has Curcuma longa Linn (Haridra) undergone Phase II trials.[26] The plant also inhibits passive The wound-healing, antiinflammatory and antimutagenic cutaneous anaphylaxis, as shown by Mahajani.[27] activities of turmeric have been demonstrated convincingly.[37] Commiphora wightii Arnott (Guggulu) However, its cancer preventive action needs to be more Commiphora wightii (guggulu), which is a major ayurvedic actively pursued. Hastak et al, have shown its beneficial effect drug, is used widely in diverse formulations. A monograph of in oral submucous fibrosis – a precancerous condition.[38] In all the major citations of its use has been published.[28] The dimethyl benzanthracene (DMBA)-induced experimental hypolipidemic effects of the plant were primarily discovered breast cancer, curcumin has shown a significant reduction in through the reverse pharmacology mode. Satyavati, carcinogenesis.[39] These effects are being investigated further Dwarakanath, Sukhdev and Nityanand have extensively studied by our group. Recently, curcumin has been shown to reduce the hypolipidemic effect of C. wightii. The product has been the plaques in Alzheimer’s disease in the animal model.[40] It already marketed and widely used.[29, 30] However, the anti­ has been stated that Indians have a lesser incidence of arthritic effects of C. wightii in clinical studies have been Alzheimer’s disease due to a steady and regular consumption relatively less investigated. We have sizeable experiential and of turmeric in their diet. The carminative effect of curcuma pharmacological studies with standardised guggulu oil was reported by Sir RN Chopra. He has also referred to a preparations. Phase I as well as long term and large dose marked diminution of the gastric acid secretion after fractional ambulant studies have been conducted. The ongoing studies test meals.[32] Hence, it may be worthwhile to study the effects at the cellular and molecular levels have helped in evolving of curcumin, turmerone, and so on, on H1 and H 2 receptors as pharmacological correlates of clinically shown actions.[31] The well as on the gastric H+K+-ATPase or the proton pump of the side effects of the plant have also been documented. The parietal cell, by the reverse pharmacology path. Several mechanisms of are yet to be studied. The plant can laboratories have demonstrated the antioxidant activities offer a platform for technological innovations in of curcumin. pharmaceutics, pharmacodynamics and . Saraca asoca (Roxb) Willd (Ashoka) The use of guggulu as a sacrificial incense (homadravya), in sacrificial use (shantikarma), is currently being evaluated for Sir RN Chopra, in his monograph on the S. asoca plant, the antimicrobial effects of the volatiles. The topical wrote, “This plant drug does not appear to have marked formulations of the plant demand unique dermato­ therapeutic effects, though many clinicians appear to vouch pharmacological reverse correlates. The different properties for its efficacy in menorrhagia and other uterine disorders”.[32] of fresh and old gum guggulu, mentioned in ayurveda Recently, Shringi et al, have shown with a formulation of literature, need additional clinical investigations both S. indica (Ashotone®), a reduction in menstrual blood loss, in experiential and exploratory. a distinct subset of menorrhagia, viz., ovulatory dysfunctional uterine bleeding.[41] The broad claims of clinical efficacy in Tinospora cordifolia Hook (Guduchi) ayurveda need to be fine tuned to the subsets of the disease In his classic, ‘Indigenous Drugs of India’, Sir RN Chopra or a syndrome. wrote, “In spite of the fact that this plant is so extensively Panchvalkal (Five barks – Ficus bengalensis, Ficus used as a household remedy and also by the Tibbi practitioners glomerata, Thespesia populnea, Ficus religiosa, Albizia lebeck) and much chemical work has been done, the pharmacological Ranjan Bhatt and her students have shown the burn- and action of the active principles isolated has not been worked wound healing activity of panchvalkal.[42] Joshi and colleagues, out. Efforts have not been made to carry out clinical trials at Bhavan’s Swami Prakashanand Ayurvedic Research Center with a view to determine its effectiveness in dyspepsia and (SPARC), have shown some significant efficacy in other conditions”.[32] Bapat et al, have shown very interesting leucorrhoea.[43] A standardised novel formulation of results with T. cordifolia in patients undergoing gall bladder panchvalkal has already been developed by Viridis

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National Seminar on Drug Standardisation in Ayurveda 2006

Date : November 6th & 7th , 2006

Place : Rajeev Gandhi Centre for Biotechnology, Jagathy, Thiruvananthapuram, Kerala

Contact address: Dr. A. Thankamma General Convenor, NSDSA Drug Standardisation Unit, Govt. Ayurveda College, Thiruvananthapuram – 695 001. Kerala Phone: 91-94475 53292

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