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Review

10.1517/17460441.2.12.1631 2007 Informa UK Ltd ISSN 1746-0441 1631


1. Introduction
2. Modern drug discovery versus
ayurvedic products-based
drug discovery
3. Ayurvedic drug discovery:
essential considerations
and requirements
4. Ayurvedic medicine: what
it can offer?
5. Ayurvedic literature
6. Recent developments in
ayurvedic medicine
7. Development of new
therapeutic compounds from
medicinal plants of Ayurveda
8. Mechanism of action of
ayurvedic drug compounds
9. Reverse pharmacology: a road
to ayurvedic drug discovery
10. Ayurvedic drug discovery:
possible present and
future directions
11. Tools and methodologies
in ayurvedic drug discovery
12. Selection criteria for herbs
and herbal preparations
13. Major challenges in ayurvedic
drug discovery
14. Ayurvedic drug development
in India: government and
private sectors
15. Conclusion
16. Expert opinion
Ayurvedic drug discovery
Premalatha Balachandran

& Rajgopal Govindarajan


University of Mississippi , National Center for Natural Products Research ,


Research Institute of Pharmaceutical Sciences , School of Pharmacy, MS, 38677 , USA
Ayurveda is a major traditional system of Indian medicine that is still being
successfully used in many countries. Recapitulation and adaptation of the
older science to modern drug discovery processes can bring renewed
interest to the pharmaceutical world and offer unique therapeutic solutions
for a wide range of human disorders. Eventhough time-tested evidences
vouch immense therapeutic benefits for ayurvedic herbs and formulations,
several important issues are required to be resolved for successful imple-
mentation of ayurvedic principles to present drug discovery methodologies.
Additionally, clinical examination in the extent of efficacy, safety and
drug interactions of newly developed ayurvedic drugs and formulations are
required to be carefully evaluated. Ayurvedic experts suggest a reverse-
pharmacology approach focusing on the potential targets for which
ayurvedic herbs and herbal products could bring tremendous leads to
ayurvedic drug discovery. Although several novel leads and drug molecules
have already been discovered from ayurvedic medicinal herbs, further
scientific explorations in this arena along with customization of present
technologies to ayurvedic drug manufacturing principles would greatly
facilitate a standardized ayurvedic drug discovery.
Keywords: Ayurveda , ayurvedic discovery , ayurvedic leads , drug discovery , medicinal plants ,
traditional medicine
Expert Opin. Drug Discov. (2007) 2(12):1631-1652
1. Introduction
Ayurveda is a traditional Indian system of medicine that includes medical
practices and beliefs as it relates to the prevention and treatment of diseases,
health, well-being and spiritual healing, in which all have evolved as a part of the
indigenous culture. ayurvedic medicinal products are time-tested over centuries
and together with recent extensive research on the medicinal chemistry, pharma-
cology and clinical aspects of many of these herbal products, their beneficial
properties are continuously proving to be useful [1] . The components used in
ayurvedic medicine provide an attractive basis for the development of novel
pharmaceutical products that can either act as active single-molecule medications
by themselves or as components of multimodel (combination of western and
ayurvedic medicines) therapeutic regimens [1] . The ultimate objective in drug
discovery is to manufacture safe and effective remedies, especially with the
immense solutions already put forth by the traditional Indian (ayurvedic, sidhha,
unani) and Chinese medicines drug discovery from herbalplant products always
remained a compelling approach [2] . Ayurvedic plants or its proven herbal
formulations could platform a foundation step for standard drug discovery
methodologies with close guidance from ayurvedic principles. Indeed, pharma-
ceutical companies in many countries, including those in developed countries, are
finding it promising to adopt strategies for therapeutic channels from what have
been long known as merely traditional remedies [3] . Ayurvedic drug discovery
cannot only offer renewal interest to the pharmaceutical world [101] , but also benefits
to patients by bringing closer-to-nature (by virtue of its source-material) and
Ayurvedic drug discovery
1632 Expert Opin. Drug Discov. (2007) 2(12)
cheaper (by cutting down the conventional drug-manufacturing
costs) forms of therapy. Although the potential benefits
envisaged from ayurvedic drug discovery are numerous, the
radical changes required for implementing them into
pre-existing standardized approaches of drug discovery pose
immense challenges [4] .
2. Modern drug discovery versus ayurvedic
products-based drug discovery
Drug discovery involves multi-disciplinary research efforts
to identify active molecules with desirable biological effects.
Major steps in drug discovery include synthesis, identification,
screening and assaying of chemical compounds. Drug
development also demands a multi-disciplinary approach,
but with a focused track to develop a single drug molecule.
It involves testing the lead molecules identified in drug
discovery processes against precisely defined target
molecule(s). Through a range of preclinical and clinical
trials, drug compounds are eventually evaluated for their
therapeutic utilities against specific diseases in humans [5] .
The present trend in the drug discovery methodology has
gotten its roots or origin from simple resources, such as
plant and mineral sources, as well as from many accidental
discoveries. Although innumerable examples of such successful
drug compounds can be readily identifiable (e.g., paclitaxel,
statins, quinine, vinblastine), the sustained enthusiasm on
the use of herbal-based resources for newer drug discovery
has only gotten dampened lately (since the early 1980s) [6,7] .
This is because of several reasons that accompany the
pace and focus of modern technological advancements in
drug discovery, the streamlined screening processes of
compound libraries, the molecular understanding on disease
processes and desirability for target-specific therapeutic
solutions [8] . Without doubt, scientific milestones, such as
the human genome sequencing and ultra-high-throughput
screening, have revolutionized present-day drug discovery
methodologies [9-11] . However, despite these advents and
transformations in drug discovery, it becomes important to
note that new drug discovery continues to act as a challenge
and successful outcomes occur only at a very slow rate
(10 years per drug on average) with extreme use of man-hours
and funding (a few billion US dollars per drug) [12] . Newer
diseases emerge all the time and existing diseases (such as
cancer, AIDS, diabetes etc.) still pose life-threatening
dangers. In the light of all of these situations, considering
alternative forms of medicines, especially from those
scientific roots that are the initial basis of todays modern
drug discovery and matured independently into valuable
medical disciplines by themselves, should prove to be highly
beneficial. Recent understanding on the human genome and
the structural characterization of human proteins are
beginning to offer clearer views by which diverse chemical
structures in plant products are acting on precise biological
targets [13] . Reinforcing further active efforts on alternate
medical utilities, especially by researching on the extent of
effectiveness and safety of their medicinal products [14] ,
could offer newer and extremely valuable directions to drug
leads. Although some pharmaceutical companies have already
marched significant strides from traditional medicinal
products, complete recapitulation of the older sciences like
Ayurveda in accordance to modern drug standards are
difficult, if not impossible. Nevertheless, continued and
renewed enthusiasm on traditional medical resources is
anticipated to bring more unique and successful remedies in
the near future.
3. Ayurvedic drug discovery: essential
considerations and requirements
Standardized ayurvedic drug discovery process necessitates
the consideration of several factors, which can be broadly
grouped under two major categories. First, it demands
incorporation of alternative steps in addition to present drug
development processes to establish a more versatile ayurvedic-
library screen [102] rather than a limiting chemical-library
screen. The prospects of this wide-screening approach could
be numerous, but essentially allow the characterization of
extremely diverse chemical compounds to successfully
identify druggable ayurvedic leads with defined biochemical
specificities [7] . Also, it has recently been reported that
natural products-based extract libraries, as opposed to existing
chemical libraries, comprise predominantly (> 90%)
compounds whose structure follows Lipinskis rule-of-five
properties [15] , which are ideal for oral administrations. Such
chemical characteristics can only be found in drug molecules
that have already made their entry to the market [7] . Second,
ayurvedic drug discovery mandates the inclusion of existing
knowledge on ayurvedic medicines and the blending of
known principles of ayurvedic science with modern drug
development technologies for more successful investigational
drugs. Based on these requirements, ayurvedic practitioners
and researchers have recently proposed many effective, yet
feasible, methods that could facilitate detailed experimenta-
tion on ayurvedic herbs and products for eventual imple-
mentation of standardized ayurvedic drug discovery
methodologies [1,16,17] . In this review, a broad outline on the
scientific aspects and resources available on ayurvedic
medicine, and its pertinence to present and potential future
drug development strategies, along with the major scientific
challenges to be faced, are discussed. Mechanistic aspects on
ayurvedic plant actions and biochemical evidences on
ayurvedic formulations, reviewed in other recent
articles [1,2,18] , are excluded.
4. Ayurvedic medicine: what it can offer?
The ayurvedic system of medicine in India dates back
to 3000 BC and prescribes remedies for a wide range of
disorders, diseases and conditions [17] . Ayurvedic classic
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1633
texts, Charak Samhita and Sushrut Samhita , describe > 700
medicinal plants [1] of therapeutic value against both
infectious and non-infectious disease conditions. These herbs
are categorized based on their appearance, taste, digestive
effects, safety, efficacy, dosage and therapeutic benefits [7] . In
India, 3000 plants of proven medicinal value are found [19] ,
and > 6000 plants are known to be used in traditional, folk
and herbal medicines [19] . An overwhelming number of
pharmaceuticals companies in India (a total of 7000)
manufacture Ayurvedic medicines along with two other tradi-
tional forms of medicines, the siddha medicines (revitalizing
and rejuvenating form of medicine developed by ancient
sages [Siddhars] for subsequent future generations) and the
unani medicines (a system of medicine based on the balance
of the elements in the body that originated 980 AD in
Persia, but was popularized in India) [20] . These indigenous
medical practices continue to prove beneficial for millions of
people in India, Sri Lanka and Nepal, despite the significant
prevalence and accessibility of western medicine. The impor-
tance of ayurvedic medicine is not only reflected in its
successful influence on other traditional systems. such as
unani, Chinese and Tibetan medicine, but also its present
modern applications in Pakistan, Bangladesh, China and
Tibet. Traditional plant medications are estimated to fulfill
nearly three quarters of all the medicinal needs of the
people in developing countries [19] , and some form of other
alternative medicines are used for therapeutic, food-additive
and cosmetic benefits by millions in developed countries.
In spite of these proven track records of traditional
medicines, a statistical analysis indicates only a poor
representation of its value in the global market and its
commonly held perception of unconventionality compared
with modern medicines [21] .
5. Ayurvedic literature
Ayurveda offers extensive information about the herbal drug
products and their therapeutic uses. The ayurvedic know-
ledge has been spread over 100 books containing > 100,000
recipes documented by ayurvedic physicians and scholars.
Besides these major resources (described later), there exist a
even larger number of recipes that are being used on a daily
basis, but are unpublished. Although the documented
ayurvedic knowledge chiefly assists ayurvedic practitioners,
by virtue of its utility they can also be used as a resource for
scientific research and drug discovery processes. Some of the
most commonly used reference materials for ayurvedic drugs
and products are given in this section.
The ayurvedic formulary of India , published by the
government of India, contains a total of 636 compound
formula tions with the volume I containing 444 formula-
tions, the volume II containing 192 formulations and the
volume III containing 192 formulations [103] . Ayurvedic
formulae and preparations include aqueous liquids, oils,
powders, tablets, pills and others ( Asava , arishta , ark, avaleh ,
kvath , curn , guggulu , grita , taila , dravak , kshara , lepa , vati ,
gutika , rasayana , parpati , bhasma , mandura , rasa yoga and
lauha ). It also includes 27 single drugs of animal origin,
42 single drugs of mineral origin, 271 single drugs of plant
origin accompanied with disease indication indices [104] .
The ayurvedic pharmacopeia of India includes in-depth
details on 326 ayurvedic plants, such as botanical names
and identification criteria, standard measures for various
parts of the plants, physical tests and determinations, quan-
titative data for vegetable drugs, limits for chlorides, sulfates,
sulfated ash, arsenic, mercury, iron, lead and other heavy
metals present in the drugs with complete official testing
methodologies [104] . A total of three volumes of ayurvedic
pharmacopeia have been published by the Indian govern-
ment, with a total of 258 monographs. A total of 80
monographs were published in the volume I, 78 mono-
graphs in the volume II and 100 monographs in the
volume III. The work on remaining single drugs of
plant, animal, mineral/metal and marine origin and
multi-ingredients formulations is presently being carried
out in 30 different ayurvedic and other scientific
research institutions [103] .
The Materia Medica of Ayurveda consists of an extremely
rich armamentarium of natural drugs, derived from the
plants, minerals, animals and marine sources. These drugs
are used as monotherapies or in simple combinations, which
are otherwise referred to as polypharmaceuticals. The forms
in which these are used are varied, such as extracted juices,
decoctions, infusions, distillates, powders, tablets, pills,
confections, syrups, fermented liquids, medicated oil,
bhasmas (resultant of incineration) and many more.
The Materia Medica of Ayurveda is an exhaustive publication
that describes simple, safe and proven remedies including
remedies for common ailments [103] .
The Treatise on Indian medicinal plants , edited by
A Chatterjee and SC Pakrashi (1991), is a five volume
treatise with each volume containing 180 325 pages.
These books contain > 800 medicinal plants. It also served
as a search engine for many scientific studies and clinical
trials conducted on ayurvedic therapies during the last five
decades [104] . A recent book on the scientific basis of
ayurvedic therapies, edited by LC Mishra, also summarizes
many of these findings [22] .
The Compendium of Indian medicinal plants , edited by
R Rastogi and BN Mehrotra, is a total of five volumes
published so far with 518 1016 pages per volume [103] .
The Indian herbal pharmacopeia (2002) contains
52 monographs on widely used medicinal plants in India
with scientific evidences on therapeutic effects.
In addition, the Pharmacopeia of India (1996) covers
additional botanical monographs on clove, guggul, opium,
mentha, senna and ashwagantha. Several other lifetime
works of many eminent pharmacologists could be found
in different ayurvedic and natural product-based scientific
institutions of India. For example, the experimental
Ayurvedic drug discovery
1634 Expert Opin. Drug Discov. (2007) 2(12)
pharmacology research works on indigenous drugs of India
conducted by Sir RN Chopra (considered as the father of
Indian pharmacology) can be found at the Regional Research
Laboratory (RRL), Jammu-Tawi [17] .
6. Recent developments in
ayurvedic medicine
Ayusoft (2004 ) is a recently developed, interactive software
that chiefly assists ayurvedic practitioners. It contains several
databases on various ayurvedic drugs along with the network
of diet patterns, lifestyles, diseases and treatment principles.
This software acts as a quick reference guide or index for
practitioners to aid in the diagnostic and treatment aspects.
The software is based on the prakruthi (ayurvedic disease
diagnosis) section of the ayurvedic texts [105] .
Ayugenomics [23] is a body of literature aimed at
understanding the ayurvedic concepts of Prakruthi from a
pharmacogenomics perspective. It offers a basis for
inter-individual variations in diagnosis, drug efficacy
and toxicity, hence the development of customized
therapeutic approaches.
Herboprint [24] uses three-dimentional HPLC and
attempts to develop tools for activity-based standardization
of botanicals.
7. Development of new therapeutic
compounds from medicinal plants of Ayurveda
The phytochemical analytical studies of ayurvedic medicinal
plants is an area of thrust and significant investigation as it
offers a direct path for the emergence of newer therapeutic
agents. Furthermore, when the structures of the active
principles are identified, it provides a platform for synthetic
and medicinal chemists to alter the efficacy or toxicity
properties or even create analogs with similar or varied phar-
macological actions. So far, among a list of frequently used
ayurvedic medicinal plants, 43% of it has undergone human
clinical trials studies and 62% of it has been subjected to
animal studies [25] . Ayurvedic drugs, such as guggul , brahmi ,
ashwangantha , amlaki , guduchi , kutki , shatavari and shunthi ,
have also shown clinical promises for therapeutic usage [25] .
In relevance to future ayurvedic drug discovery, one could
categorize ayurvedic plants as follows:
Those on which sufcient leads are available and their
biological targets are known. Some well-known ayurvedic
leads and their molecular targets for cancer therapy are
discussed in detail in a recent review by Aggarwal et al. [18]
and a summary of ayurvedic plants and their biological
targets are listed in Table 1 .
Those with proven medicinal value and with considerable
availability of scientic evidences ( Table 2 and 3 ).
Those with signicant potentials to offer novel drugs,
but for which substantial experimentation needs to be
performed (see Section 12).
8. Mechanism of action of ayurvedic
drug compounds
Ayurvedic system of medicine is founded on the principle
that disease occurs due to the derangement of the functional
vital energies in the body ( vata [air + ether] or the kinetic
energy; pitta [fire] or the thermal energy and kapha
[earth + water] or the potential energy), as well as the loss
of mutual coordination between them. ayurvedic drugs are
formulated to rejuvenate the deranged state to a healthy
state so to restore the harmony between body and nature.
The extreme chemical diversity of compounds in ayurvedic
drug formulations simultaneously targets most systems
of the body, resulting in an array of potent and diverse
biochemical outcomes. Many scientific studies corroborate
ayurvedic principles and the basis for ayurvedic drug action
have been extensively reviewed recently [18,22,26,27] . Based on
the scientific literature published so far, it also becomes evident
that some of the components used in ayurvedic formula-
tions or multi-herb extracts do not possess major biological
activities by themselves, but instead act as potenti ators or
moderators of the efficacy and toxicity effects of the major
active principles. For example, non-therapeutic components,
such as milk and ghee, are added to Semecarpus anacardium
formulations to moderate its hot, acrid and dry nature [28,106] .
Similarly in amalaki ( Emblica officinalis )-based rejuvenators,
such as chyavnan prasha avaleha , although amalaki is the main
ingredient, the formulation contains > 25 herbs that are
added for synergistic and counter-balancing effects. In
addition to that, a sweetener, such as raw sugar or honey
that has no biological activity, has been added to moderate
its pungent taste. The herbs in this preparation insure that
the sweet is properly digested and cause no adverse
reaction [107] . Triphala , another ayurvedic formulation, is a
combination of amla ( Emblica officinalis ), bibhitaki
( Terminalia belerica ) and haritaki ( T. chebula ), in which all
these three herbs act synergistically as laxative and helps
digestion [108] . Thus, multi-ingredient herbal compounds in
ayurvedic sciences are rendered both effective and safe in
treating human ailments. Although these principles have
been shown to successfully offer prevention and treatment
of many diseases, it also reminds the confounding issues of
new drug discovery from ayurvedic herbs (standardization
and precise utilization of various herbal components in the
generation of active drug formulations) [14] .
9. Reverse pharmacology: a road to
ayurvedic drug discovery
Although conventional drug discovery starts with lead
identification and optimization followed by in vivo
pre clinical studies (Phase I) and human clinical trials
(Phase II and Phase III), ayurvedic drug discovery
was recently proposed [29] to preferably work in a reverse
pharmacology direction with stages described in Figure 1 .
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1635
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Expert Opin. Drug Discov. (2007) 2(12) 1637
The advocation of reverse pharmacology in ayurvedic
sciences was initiated by eminent vaidyas , including
Mahamahopadhyaya Gananath Sen [17] , and since then has
evolved as a powerful scientific approach for newer drug
discovery. The reverse pharmacology approach is described
by Ashok DB Vaidya as a newer academic discipline that
integrates documented clinical and experimental hits with
leads by trans-disciplinary exploratory studies. The further
development of leads into drug candidates is triggered
by experimental and clinical research. Thus, ayurvedic
drug discovery follows a retrogressive path based on clinical
observations noted with herbal products.
The Indian Council of Scientific and Industrial Research
(CSIR) and the Indian Council for Medical Research
(ICMR) have successfully conducted many clinical trials
based on reverse-pharmacology and their respective directors
have detailed the prospects of this approach in national
and international forums [109] for future drug discoveries.
Some of the plants that have been successfully analyzed
by this approach include Mucuna pruriens for Parkinsons
disease, Zingiber officinale for nausea/vomiting, Picrorhiza
kurroa for hepatitis, Curcuma longa for oral cancer,
Panchavalkal spp. for burns and wounds and Azadirachta
indica for malaria.
10. Ayurvedic drug discovery: possible
present and future directions
Recent trends indicate that ayurvedic drug discovery and
therapeutics can take several possible reverse-pharmacology
Table 2 . List of Ayurvedic botanicals with potential for drug discovery [103] .
Botanical name Ayurvedic/ Common
Name
Disease conditions
Acorus calamus Vacha Obesity, hypertension, speech disorders, sedative, transquilizer, mental distress
Adhatoda zeylanica Vasa Bronchiolar constriction
Anethum sowa Soya Appetiser, carminative
Asparagus racemosus Shatavari Aphrodisiac, dysuria, galactogogue, leucorrohea, peptie ulcer
Azadirachta indica Nimba Gastritis, bleeding piles, wounds, fumigative, disinfectant against
bacterial and viral infections
Berberis aristata Daruharidra Liver disorders, conjuctivitis, dysentery, anti-pyretic,
antiperidoic, diaphoretic
Boerhaavia diffusa Punarnava Eye diseases, diabetes, anti-diuretic, hepatoprotective, inammation
Crataeva nurvala Varuna Erysipelas, lymphadenopathy, urolithiasis
Cassia augustifolia Rechani, markhandi Severe constipation
Centella asiatica Mandukparni Neurological problems
Commiphora wightii Balsamodendron mukul Arthritis
Emblica ofcinalis Amalaki (Amla) Anaemia, jaundice, haemorrhage, acidity, immune stimulant
Eugenia jambolana Jamboo Diabetes
Ferula foetida Hingu (Heeng) Septic conditions, digestive stimulant, expectorant, carminative
Mallotus philippinensis Kampillak (Kamila) Anthelminthic, aphrodisiac
Moringa oleifera Shigru (Sehanjana) Abcess, septic conditions, wound healing, piles, inammation,
neuritis, joint diseases
Myristica fragrans Jaiphal Nausea and vomiting, diarrhea, leucorrhoea
Nelumbo nucifera Kamal beej/Kamal Gatta Hypoglycemic
Piper longum (root) Pippalimool Malaria, insomnia, worms, piles
Phyllanthus emblica amla Anti-ageing
Psoralea corylifolia Bakuchi Vitiligo, bronchial asthma
Saraca asoca Ashok Meno-metrorrhagia, neurological disorders, spasmogenic, uterine infections
Terminalia arjuna Arjun Cardiac disorders
Terminalia chebula Haritaki (harad) Laxative
Trachyspermum ammi Yavani Anthelminthic, spasmogenic carminative
Tribulus terrestris Goksura (Gokkru) Diuretic, aphrodisiac, lithontriptic
Ayurvedic drug discovery
1638 Expert Opin. Drug Discov. (2007) 2(12)
Table 3 . Classication of botanicals according to their efcacy towards various diseases.
Health disorders Botanicals with scientic evidence
Allergies [52] Cleodendrum seratum, Benincasa hispida, Aquilaria agallocha, Albizzia lebbeck, Curcuma longa,
Inula racemosa, Galphimia glauca, Picrorhiza kurroa, Adhatoda vasica
Alzhemiers disease [53] Bacopa monniera, Centella asiatica, Convolvulus pluricaulis, Eugenia caryophyllus,
Glycyrrhiza glabra, Hydrocotyl asiatica, Lawsonia inermis, Nardostachys jatamansi, Poenia emodi,
Pongamia pinnata, Tinospora cordifolia, Withania somnifera
Antimutagens [54] Terminalia arjuna/chebula/bellerica, Ocimum sanctum, Glycyrrhiza glabra, Semecarpus anacardium,
Embilica ofcinalis, Cinnamomum cassia, Withania somnifera, Centella asiatica
Arthritis [55] Vanda roxburghii, Commiphora mukul, Semecarpus anacardium, Crataeva nurvala,
Hemidesmus indicus, Andrographis paniculata, Aglaia roxburghiana
Bronchial asthma [56] Picrorrhiza kurroa, Solanum spp, Tylophora indica, Boswellia serrata
Cancer
(benign and malignant) [57]
Withania somnifera, Aloe vera, Coleus forskohlii, Andrographis paniculata, Santalum album,
Picrorrhiza kurroa, Semecarpus anacardium, Ocimum sanctum, Calotrophis procera,
Plumbago rosea, Nigella sativa, Embilica ofcinalis
Colon diseases [58] Zingiber ofcinale, Acorus calamus, Aegle marmelos, Withania somnifera, Bacopa monniera
Constipation [59] Aloe vera, Plantago ovata, Cassia senna, Rheum ofcinale, Prunus persica, Terminalia chebula,
Cassia stula, Mallotus philippinensis, Ricinus communis
Dermatophytes [60] Cassia tora, Hydnocarpus laurifolia, Pongamia pinnata, Argemone mexicana, Ricinus communis,
Plumbago zeylanica, Psoralea corylifolia
Diabetes mellitus [61] Momordica charantia, Trigonella foenum, Coccinia indica, Pterocapus marsupium, Ficus bengalensis
Diarrhea and dysentery [62] Holarrhena antidysenterica, Myristica fragrans, Dioscorea oppositifolia, Psidium guajava,
Musa paradisiaca, Nelumbo nucifera, Ficus bengalensis, Acorus calamus, Clerodendrum phlomidis,
Piper nigrum, Berberis aristata, Punica granatum, Tinospora cordifolia, Calotrophis procera,
Valeriana ofcinalis
Emetics [63] Azadirachta indica, Randia dumatorum, Cucumis sativus, Luffa echinata, Embelia ribes,
Salix caprea, Toddalia asiatica, Pongamia pinnata
Enema [63] Randia dumatorum, Holarrhena antidysenterica, Saussurea costus, Luffa echinata,
Acorus calamus, Aegle marmelose
Epilepsy [64] Withania somnifera, Semecarpus anacardium
Gastroduodenal ulcers [65] Musa sapientum, Bacopa monniera, Eclipta alba, Abies pindrow, Benincasa hispida,
Centella asiatica, Convolvulus pluricaulis, Pongamia pinnata, Garcinia indica, Zingiber ofcinale,
Asparagus racemosus, Aegle marmelos
Gynecological disorders [66] Saraca indica, Aloe vera, Glycyrrhiza glabra, Curcuma longa, Nardostachys jatamansi, Zingiber ofcinale,
Commiphora mukul, Withania somnifera, Tinospora cordifolia, Asparagus racemosus
Heart diseases [67] Terminalia arjuna, Aloe vera, Coleus forskohlii, Inula racemosa, Andrographis paniculata,
Centella asiatica, Piper longum, Picrorhiza kurroa, Commiphora mukul
Hepatic disorders [68] Andrographis paniculata, Annona atemoya, Boerhavia diffusa, Eclipta alba, Terminalia chebula,
Semecarpus anacardium, Phyllanthus niruri/amarus, Picrorrhiza kurroa, Podophyllum hexandrum,
Tinospora cordifolia
Thyroid dysfunction
(hyperthyrodism) [69]
Azadirachta indica, Momordica charantia, Convolvulus pluricaulis, Emblica ofcinalis,
Ocimum sanctum, Piper betel, Rauwola serpentina, Trigonella foenum, Moringa oleifera,
Lithospermum ofcinale, Lithospermum ruderale, Allium sativum, Nelumbo nucifera, Aloe vera,
Aegle marmelos
Thyroid dysfunction
(hypothyroidism) [69]
Bauhinia variegata, Echhornia crassipes, Bauhinia purpurea, Commiphora mukul,
Withania somnifera, Achyranthes aspera, Saussurea lappa
Hyperacidity [70] Embilica ofcinalis, Glycyrrhiza glabra, Asparagus racemosus, Eclipta alba, Trichosanthes dioica,
Adhatoda vasica, Cocos nucifera
Immune modulation [71] Terminalia chebula, Embilica ofcinalis, Piper longum, Gycyrrhiza glabra, Allium sativum,
Commiphora mukul, Tinospora cordifolia, Withania sominifera, Aloe vera
Indigestion [72] Zingiber ofcinale, Foeniculum vulgare, Curcuma longa, Mentha piperita
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1639
tracks, with overlapping steps with each other. The following
are three major tracks that are anticipated to progress at an
increased pace in the near future.
i) New drug discovery, or more particularly widespread
use of known ayurvedic drugs, could result as a natural
direction when ayurvedic medications with proven abilities
are further subjected to well-designed and analyzed human
clinical trials. In this approach, ayurvedic formulations per se
are scrutinized for the extent of efficacy and toxicity using
precise biological and clinical end point assays, critical
drug interactions and inter-individual variability measures.
This method is quite feasible in countries where ayurvedic
medicines are commonly practiced and where there is a
drive for more use of natural medicines in place of conven-
tional medicines that are either less effective or ineffective
for a given problem. Such an approach would also be
ideal for promising ayurvedic formulations that are not
amenable for standardized in vitro biological assays (e.g., cell
culture-based) and other laboratory-based exploratory studies.
However, whenever the use of in vivo methodologies (such
as whole-animal studies) that have traditionally been used
to test ayurvedic products are possible, they should be
Table 3 . Classication of botanicals according to their efcacy towards various diseases (continued).
Health disorders Botanicals with scientic evidence
Male reproductive disorders [73] Asparagus racemosus, Cynomorium coccineum, Mucuna pruriens, Piper longum,
Tribulus terrestris, Trichopus zeylanicus, Vanda tessellata, Withania somnifera, Zingiber ofcinale
Obesity [74] Commiphora mukul, Terminalia chebula, Terminalia belerica, Embilica ofcinalis,
Picrorrhiza kurroa, Curcuma longa, Plantago ovata
Parkinsons disease [75] Withania somnifera, Bacopa monniera, Centella asiatica, Sida cordifolia,
Mucuna pruriens
Psychiatric disorders [76] Withania somnifera, Ocimum sanctum, Bacopa monniera, Convolvulus pluricaulis,
Centella asiatica
Purgatives [63] Picrorrhiza kurroa, Ricinus communis, Terminalia chebula, Terminalia belerica,
Embilica ofcinalis, Euphorbia neriifolia, Indigofera tinctoria, Cassia stula
Sciatica [77] Commiphora mukul, Vitex negundo, Ricinus communis, Pluchea lanceolata,
Sida cordifolia, Tinospora cordifolia
Urolithiasis [78] Crateva nurvala, Tribulus terrestris, Bergenea ligulata
Exploratory stage
Tolerability studies
Doseresponse studies
Druginteraction studies
In vitro and In vivo assays
for Safety and Efficacy
Experimental stage
Molecular targets
Signaling pathways
Receptor pathways
Structure elucidation and
Crystallization of drug-target
complexes
Experiential stage
Diagnosis
Documentation
Follow-up
Clinical observations
Figure 1 . Reverse pharmacology approach for ayurvedic drug discovery.
Reverse pharmacology concept adapted from Patwardhan et al. (2004) [1] and Vaidya (2002) [29] .
Ayurvedic drug discovery
1640 Expert Opin. Drug Discov. (2007) 2(12)
OH
HO
HO
O
OH
Gallic acid
Vascine
S
S
O
Allicin
N
N
OH
S
O
O
OH
OH
OH
H
S
E
R
S
S
R
R
Andrographolide
O
O
OH
HO OH
O HO
O
OH
Bacoside A
O OH
H
H
H
HO
S
S
R
R
R
R
R R
R
R
R
Boswellic acid
O
O
H H
H
S
R R
S S
Z
Guggulosterone
O O
O
HO
O
OH
E E
Curcumin
O
HO
Eugenol
O
O
O
O
OH
H H
H
OH
HO O
OH
H
O
OH
OH
OH
HO O
O
H
R
R
R
R R
R
R
S
S
S
S S
S
S
S
S
S
S
S
Glycyrrhizin
HO
HO
OH
O
NH
2
S
L-dopa
O
O
O
O
OH
OH
HO
HO
Ellagic acid
N
O
O
O
E E
Piperine
O
O
O
O
OH
HO OH
H
O
OH
H
H
O
OH
E
R
R
R
S
S
S
S
S
S
S
S
Kutkoside
N
H
N
O
H
H
H
O O
O
O
O
O
O
O
S
S
S
R
R
R
Reserpine
OH
HO
OH
E
Reservatol
O
H
OH
O
S
S
S R
Tinocordifolin
O O
O
H
H
O
O
H
H
H
S
S
S
S
S
S
R
R
R
Withaferin A 8-Gingerol
HO
O
O OH
4
S
6-Gingerol
HO
O
O OH
6
S
Figure 2 . Structures of Ayurvedic leads.
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1641
adequately used to validate ayurvedic products before
escalating to human clinical trials.
ii) Ayurvedic medications per se are subjected to a
higher level of (more rigorous analysis than the previous)
scientific exploratory studies comprising both in vitro / ex vivo
components (metabolic and activity evaluation assays) and
in vivo (preclinical and clinical) components. Heterogeneous
crude extracts containing a mixture of compounds
(2 100 compounds) are subjected to biological activity-
based (e.g., whole animal model testing for response
elicitations) or assay-based screening (e.g., antimicrobial
challenge studies) and fractionation methods. These response-
based studies narrows down complex mixtures to single-
molecule or fewer-combination (2 10 compounds)
mixtures. The subsequent validation of these refined prepa-
rations for efficacy and toxicity studies by human clinical
trials for the diseases originally targeted by the ayurvedic
formulations should be conducted. Identification and
isolation procedures in this approach would probably involve
several rounds of chemical purification as well as synthesis
measures to scale-up drug compounds. Approximately, lower
milligram (1 10 mg) levels of active compounds are
required for bio-assaying and at least a few grams (1 10 g)
of pure or semipure compounds are required for lead
identification [30] . Such an approach is suitable for both
proven and potential forms of Ayurveda therapeutic
formulations and can be conducted at any place where the
quantity and quality of the authentic ayurvedic drug
products is not a problem. Difficulties in this approach
could arise when more than one compound at varying orders
of concentration is responsible for a desired biological or a
therapeutic response, which is many a time the case with
ayurvedic herbs. In that case, even extensive end point
characterizations (such as K
i
or IC
50
values for a potential
enzyme inhibitor) of many of the active components in a
mixture may not sufficiently identify discernible clues for a
therapeutically effective few-compound mixture.
iii) The last track is the elementary analysis of ayurvedic
herbs (and not ayurvedic products) that are described in
ayurvedic texts and pharmacopeias, for identification and
isolation of active single-molecule drugs. Being an exhaus-
tive venture for identifying active and potent single mole-
cules, the procedure becomes quite complex for certain plant
compounds that tend to occur as bonded complexes with
similarly structured and often inactive compounds. If the
molecular profiling of active ingredients is successful, then
these catalogued compounds can be subsequently subjected
to conventional drug discovery steps. The beginning step,
which extensively use combinatorial screening library of
compounds from ayurvedic plant extracts is excepted. As
mentioned in the previous approach, over coming difficulties
posed by the multi-active ingredients that are present at
varying orders of concentrations (and contributing to
different levels of therapeutic benefits) need to be
carefully considered. Even though this approach has
higher probability of identifying single-molecule active
compounds from designated ayurvedic herbs (e.g., curcumin
in turmeric, guggulosterone from guggul), it also suffers
the selective disadvantage of not taking into account
the supplemental benefits offered by trace-levels compounds
additionally present in those herbal plants (as opposed to
original ayurvedic preparations). Such an approach is also
feasible in any part of the world provided the resources,
infrastructure and methodology are available.
The first two processes are shot-gun approaches to make
an extensive use of the known properties on the ayurvedic
plants and medications and bring ayurvedic formulations
to the market in a relatively shorter period. It encompasses
optimistic approaches to find superior ayurvedic formula-
tions and drug products among the existing herbal
preparations or even to develop new drug compounds.
Multi-ingredient mixtures are also gaining significance in
the drug discovery field because they yield drug preparations
of superior clinical value compared with monotarget drugs.
However, in the light of the lack of available data on the
successful use of ayurvedic products in different ethnic
population, metabolic enzymes involved in detoxifying
ingredients and toxicity issues need to be carefully considered.
The last approach uses the pharmacognostic sources of
ayurvedic drugs for streamlined drug discovery approaches,
beginning with the identification of the active compounds
from ayurvedic plants. Even though this approach is intensely
time consuming, relatively expensive and requires major
modifications in the early drug discovery methodologies, it
has a higher probability of identifying novel drug molecules
or chemical structures for experimentation on directed
structural alterations and lead optimizations.
11. Tools and methodologies in
ayurvedic drug discovery
The evaluation of ayurvedic herbs (or products) lays out
several stages that demand the use of modern analytical
tools for compound screening and analysis. The mixture of
compounds in multi-ingredient formulations or in ayurvedic
plants often requires to be simplified into simple and pure
(or semipure) single- or fewer-combination molecules. This
is achieved by preparing concentrated ayurvedic plant
extracts and fractionating and purifying them into sufficient
quantities for assaying purposes. Recent high-resolution
separation technologies, such as HPLC and tandem mass
spectrometry have indeed revolutionized compound
separation and fractionation procedures in a relatively
time-conserving manner. The HPLC effluents can be directly
ionized (electrospray ionization or atmospheric pressure
ionization) and can be further analyzed by mass spectrometry
techniques [31] (e.g., Fourier transform ion cyclotron
resonance mass spectrometry) for a precise determination of
molecular masses and other relevant compound parameters.
On the other hand, high-resolution NMR spectroscopy
Ayurvedic drug discovery
1642 Expert Opin. Drug Discov. (2007) 2(12)
analysis could greatly facilitate analysis or even could help the
elucidation of the structure of novel ayurvedic compounds.
An array of sophisticated analytical techniques [32] (e.g.,
ultra-pressure liquid chromatography, supercritical fluid
chromatography, capillary electrophoresis), combinatorial
techniques (e.g., high-resolution mass spectroscopy with
two-dimensional NMR) and high-throughput online assays
(continuous-flow enzymatic analysis) that are presently
used in conventional drug discovery processes can also be
customized for ayurvedic drug discovery processes. Although
these modern instruments will surely facilitate the chemical
analysis of ayurvedic compounds at an incredibly rapid pace
and with lower amounts (nanogram or lower microgram
levels of pure compounds), chemical derivatizations guided
by structureactivity relationships and traditional medicinal
chemistry approaches can also be used wherever scaling-up
becomes a factor. For compounds exhibiting absolute
difficulties for the purification from ayurvedic plant matrices,
circumventing measures could be taken to assay and market
them as fractionated or semipurified complexes.
12. Selection criteria for herbs and
herbal preparations
One of the major points, which often also becomes an
issue that has to be carefully considered in ayurvedic drug
discovery, is the nature of the source materials. The selection
of potential herbal leads would essentially depend on several
selection criteria. These include relevance to disease preva-
lence and thrust areas of present research where therapeutic
alternatives are not available, easy availability of ingredients
and raw materials, necessity for single- or multi-ingredient
formulations, modes of compound extractions and purifica-
tions, desirability for wide-spectrum benefits within a
range of disorders, innovativeness in the material used,
shelf-life required for the newer ayurvedic formulations,
extent of efficacy and toxic side effects, scope for commercial-
ization and availability of previous preclinical and clinical
data [110] on those ayurvedic compounds. Additional
factors that have to be considered in ayurvedic drug
discovery, but not necessarily in conventional drug discovery
processes, are the use of appropriate plant parts (e.g., leaves,
barks, dried roots), the preparatory forms (powders, enriched
extracts, tender shoot extracts etc.) and the processing
methods and durations (shade-dried leaves, freshly harvested
seed-pods etc.).
Several workshops and conferences are now conducted in
different parts of India for an active implementation of
research and clinical validations of ayurvedic plants described
in ayurvedic texts. A recently held National Innovative
Foundation workshop on ayurvedic drugs (2004) has
concluded that the selective herbs listed in Table 4 should be
used for various disease conditions [110] . In concurrence to
that, several Indian scientific research institutes have agreed
to conduct clinical trials on these medicinal plants.
13. Major challenges in ayurvedic
drug discovery
Ayurvedic drug discovery beginning with elementary
analysis of ayurvedic plants is one of the main approaches
that have received significant attention so far in new
drug discovery. Even with this approach, the time consumed
from compound analysis and cataloging of ingredients to
manufacturing final drug products is enormous. Many
a time, enthusiasm in this approach weakens when the
multi-component beneficial activity of herbal medicines can-
not be closely or even nearly reproduced by single-molecule
or fewer-combination drugs. Compared with this approach,
other proposed approaches for developing modern medica-
tions from ayurvedic formulations lag behind even in terms
of clinical initiatives. Much of this is because of the inherent
technical difficulties in understanding and implementing the
ayurvedic theories to present drug manufacturing and drug
delivery practices. The lack of expertise to develop and
produce these formulations on a large scale basis and
successful fitting of available ayurvedic resources to present
high-through screening methodologies, creates additional
hindrances [33] . In addition, difficulties in conducting the
pharmacokinetic, pharmacodynamic and bioequivalence
studies with specialized ayurvedic formulations also signifi-
cantly retard new drug discovery ideas. Moreover, the lack
of precise pharmacological end points of multi-ingredient
formulations and massive interferences by fluorescent and
light-scattering compounds in ayurvedic formulations, bring
daunting difficulties in assay developments. Furthermore,
the lack of characterized animal models for preclinical
examination of ayurvedic formulations poses a new type of
challenges. One other general limitation is the failure of
ayurvedic disease descriptions and treatment modalities to
comply with perfect curative paths in the present days
scenarios. This is because of differences in the disease forms
described in ayurvedic texts as opposed to the present-world
disease presentations. The complexities in understanding the
older nomenclatures, disease descriptions, and their correla-
tion to modern disease symptoms and courses also pose
inconveniences. The changes in the properties of the
medicinal plants due to alterations in soil conditions,
climatic factors and other environmental reasons over time
also complicate the ayurvedic drug discovery issues. Studies
on the Saraca asoca plant, which was broadly described in
ayurvedic texts as an effective herb for menorrhagia and
other uterine problems, had only shown to be therapeuti-
cally effective against ovulatory dysfunctional uterine bleeding
in recent clinical trials and not for other types of uterine
dysfunctions [34,35] . Although the multiple factors described
above could very well contribute to such inaccuracies, finely
tuned recharacterizations of the ayurvedic plants for precise
therapeutic effects and outcome become a major necessity.
Although the above-mentioned factors definitely create
hurdles in handling the ayurvedic sources for drug discovery,
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1643
Table 4 . Selective herbs that should be used for various disease conditions, as concluded by the Indian National
Innovative Foundation workshop on ayurvedic drugs (2004) [110].
Disease/disorder Medicinal plant
Gastrointestinal and hepatic
diseases and disorders
Peptic ulcer
Hyperacidity
Constipation
Murraya koenigi (leaf)
Aristolocehia bracteata
Ricinus communis
Aeglemarmelos + Cynodon dactylon + Eclipta alba
Diarrhoea
Liver damage
Jaundice
Abutilon indicum
Asparagus racemosus + rice grain
Solanum tilobatum
Zingiber ofcinale
Cassia sophora
Justicia gendurussa
Cascaria esculenta + Phyllanthus fraternus
Citrus limon + Ervattamia heyneana
Pergularia daemia + rice grain
Coccinia indica
Gymnosporia spinosa
Dermal problems (including burn
injury, sepsis, eczema, herpes
infection and leucoderma)
Heritiera littoralis
Ervattamia heyneana
Azadirachta indica
Maytenus emarginatus
Piper betel
Euphorbia hirta + Madhuca indica
Aneilema nudiora + Aquilaria agallocha + Citrus limon
Lawsonia inermis + Santalum album
Azadirachta indica
Cyclea peltata+ Cocos nucifera
Allium sativum + Musa sp. + Nicotiana sp.
Andrographis alata
Semecarpus anacardium + Ricinus communis
Vernonia cineria
Diabetes Holarrhena pubescens
Ficus racemosa + Prosopis juliora + Sapindus laurifoius +
Bougainvillea spectabilis
Ficus glomerata
Aristolochia bracteata
Odema and urinary infections Oedema of legs
Urinary infection
Daemia extensa
Dracena terniora
Miscarriages and infertility Abortion prevention
Frequent miscarriage
Citrus limon + Ixora nigricans
Aegle marmelos + Putranjiva roxburghi
Aristolochia bracteata
Respiratory disorders and
miscellaneous diseases
Cough
Cough and asthma
Cuminum cyminum + Piper nigrum + Zingiber ofcinale
Allium sativum + Cissus quadrangularis + Piper nigrum
Adhatoda vasica + Cuminum cyminum + Coriandrum sativum
Piper betel + Zingiber ofcinale
Infant cough
Asthma
Aegle marmelos + Zingiber ofcinale
Allium sativum + Chenopodium album + Cuminum cyminum +
Piper longum + Sachharum ofcinarum + Syzygium aromaticum +
Zingiber ofcinale
Cinnamomum verum + Curcuma longa + Elettaria cardamomum +
Syzygium aromaticum + Zingiber ofcinale
Ayurvedic drug discovery
1644 Expert Opin. Drug Discov. (2007) 2(12)
none of it necessarily poses a complete technical impasse for
ayurvedic drug discovery. However, there are few immediate
and practical challenges, viz availability of the ayurvedic
source materials, clinical evaluation of efficacy and safety of
ayurvedic medicines, problems on ayurvedic drug formula-
tions and ayurvedic drugdrug interactions, which would
require more serious considerations for ayurvedic drug devel-
opment initiatives. These critical issues are discussed at
length in the following sections, along with some possible
alternatives to overcome such shortcomings.
13.1 Availability of raw materials for an
ayurvedic discovery path
Any drug discovery process mandates availability of source
raw materials that are adequately and qualitatively sufficient
to obtain enough active principles both for initial clinical
evaluation and for further scaling up processes to meet the
market demand. The major source for ayurvedic drug
discovery is the medicinal plants described in ayurvedic
texts. Clear shortage of required raw materials is one of the
major reasons why reverse-pharmacology approaches are less
commonly practiced in drug discovery processes. Technical
limitations to produce desired amounts of active components
even when medicinal plants are adequately available pose
another key issue for the ayurvedic pharmaceutical industries.
Naturally, this constraint is carried on as a failure to meet
required market demand even when the drug product proves
to be therapeutically effective in clinical trials. Alternate
initiatives that could circumvent inadequacy problems
include either synthetic or semisynthetic development of the
plant drug compounds [36,37] . Guggul, an antichloesetrol
drug isolated from Commiphora mukul , is one of the
best examples for such synthetic versions developed in
circumventing inadequacy or supply problems [7] .
Although the availability of the resource for some medicinal
plants is not a problem, heavy metal contaminations and
alterations in ingredients due to other environmental
pollutants can make them difficult or unsuitable for drug
development [38,39] . Additional issues include segregation
of phenotypically identical plants and identification of
differences within a plant type (variability factors within a
species) [2] . Recent developments in molecular characteriza-
tion studies not only greatly facilitate the understanding of
the species and genetic variability in medicinal plants,
but also help in dissecting finer plant properties including
contraindications and quality-control measures [11] . In this
regard, Indian drug manufacturers generally follow the
World Health Organization guidelines for identifying heavy-
metal and mycotoxin contamination, adulterations in plant
products and for processing techniques including harvesting
and storage requirements [20] .
Distinct plant breeding strategies for conservation of nearly
extinct medicinal plants, large-scale cultivation of medicinal
plants for bulk production, understanding of habitats role
(climatic, soil and other environmental influence) on the
composition and content of medicinal plants, incorporation of
modern processing and storage methods and implementing
strict quality-control standardization methods are some
of the efforts needed to generate quality raw materials
from rare ayurvedic plants showing promise for new
drug discovery. Cross-breeding and plant biotechnology
techniques (genetic transformation, micropropagation
tissue culture, cryopreservation) could also diversify the
medicinal value of well-studied ayurvedic plants [4] . Selective
enrichment of desired plant components or reduction
of toxic plant components by genetic engineering
techniques should also be practiced for better
resource managements.
13.2 Clinical evaluation of efcacy and
safety of ayurvedic medicines
The ayurvedic drug formulations are based on medicinal
plant extracts and products that have been safely used for
thousands of years. For most part, this assures a time-tested
selection process for various plant drugs available in the
ayurvedic pharmacopeias. However, ayurvedic medicinal
preparations (liquid kashayams [aqueous or oily extracts]
or powders) often use extremely low concentrations of
active ingredients and many of these ingredients have
been shown to operate in conjunction (by covalent or
Table 4 . Selective herbs that should be used for various disease conditions, as concluded by the Indian National
Innovative Foundation workshop on ayurvedic drugs (2004) [110] (continued).
Disease/disorder Medicinal plant
Bronchial asthma
Dry cough and asthma
Bronchitis
Ear pain and tooth ache
Ear pain
Cold
Acorus calamus + Glycyrrhiza glabra + Sida stipulata +
Trigonella foenum-graceum
Arum sp. + Piper nigrum + Nigella sativa + Zingiber ofcinale
Curcuma longa + Rubia cordifolia + Zingiber ofcinale
Pongamia pinnata
Azadirachta indica + Hemidesmus indicus + Vitex negundo
Acorus calamus + Allium sativum + Azadirachta indica +
Ferula asafoetida
Ocimum sanctum + Piper nigrum
Ocimum sanctum + Zingiber ofcinale
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1645
non-covalent bonding) with other natural substances (e.g.,
tannins, carbohydrates, minerals) in the body. The key goal
in ayurveda-based drug discovery is the development of a
single-molecule or a fewer-combination drug formulations
that faithfully represents the drug actions noticed in tradi-
tional multi-ingredient ayurvedic formulations. Although
ayurvedic texts mention that multi-ingredient formulation
can overcome key therapeutic drug delivery issues, such
as low bioavailability, and less potency, it can also pose
serious disadvantages including susceptibility to toxicities
(hepatotoxicity and nephrotoxicity) and drugbotanical
interactions especially in the light of present-day diet,
environ ment and lifestyle patterns. Also, the active
parent-drug molecules and the metabolites of each of these
parent drug compounds complicate the pharmacokinetic
understanding of multi-ingredient formulations, which
would become easier when single or fewer-combination
drug molecules are developed. Sometimes the isolated new
compounds may not completely comply with original
ayurvedic descriptions and, hence, it might become essential
to revalidate their efficacy and safety by in vitro/in vivo
studies and clinical evaluations. Although extensive
clinical evaluation as used in conventional drug discovery
(such as randomized clinical trials) may not be feasible
all the time for ayurvedic drug products, a carefully
designed case-study process could help addressing if activity
and safety are attained within measurable parameters. Case
study trials essentially evaluate the traditional uses of a
drug in the existing clinical settings and have also been
recommended by the NIH and the National Center for
Complementary and Alternative Medicine [40] for ayurvedic
practitioners. The knowledge available from ayurvedic
literature can guide the usual ethical considerations and
dose and dosage forms. For all new (single) molecular
entities identified from ayurvedic plants, the dose and
dosing-regimens are evaluated based on therapeutic
concentrations, elimination pathways and pharmacokinetic
parameters (bioavailability, clearance, volume of distribution,
half-life, plasma-protein binding, AUC). These processes
closely follow and parallel conventional drug pipeline
assays as well as help to consolidate resources in a manufac-
turing unit. In cases and diseases (e.g., cancer) where
single-molecule compounds fail to offer adequate therapeu-
tic solutions and where ayurvedic theories firmly
support multi-drug treatment modalities [26] , further clinical
evaluation for potency and toxicity studies could be
planned in the presence of one or more secondary
active ingredients.
13.3 Problems on ayurvedic drug formulations,
dosage and delivery, and their evaluation
Ayurvedic formulations are often dispensed in specialized
preparations, such as arka (saturated aqueous solutions
prepared by distillation), asava (non-boiled fermentation
products), arishta (boiled fermentation products), churnams
(fine powders), ghrithams (ghee preparations), lehyams
(jaggary syrup preparations), lepam (ointments), panakam
(aqueous extracts), thailam (medicated oils), bhasma
(incinerated metals or minerals), sinduram (drugs prepared
by sublimation) etc . On the contrary, modern drugs require
convenient formulations mainly in the form of tablets,
capsules, injectables or oral-liquid (syrups) preparations.
A heavy-metal content of ayurvedic medicine has been
another hot topic of concern for its consumers, especially
after the publication of reference [38] in the Journal of
American Medical Association. In ayurveda, there is a class
of medicine called rasaushadha (herbo-mineral/metallic
formulations) that contains minerals and metals in the
form of bhasmas (incinerated metals) in addition to herbs.
Ayurveda clearly recognized and established all the symptoms
of heavy metal toxicity at least 3000 years ago, and
has advocated stringent standards to use the metals
therapeutically only after eliminating its toxic effects by
processing [111] . Rasa shastra is the section which describes
the use of metals, gems, minerals in formulations to treat
incurable chronic diseases. These non-herbal ingredients are
first purified and then burnt several times and converted
into ash ( bhasma) . Some of the metals are burnt up to
100 times to nullify their toxic effects. These ultra-fine
particles should be able to float on water, which indicates
the non-existence of heavy metals in the preparation.
Although modern chemical testing may give positive result
for the presence of heavy metals, according to Ayurveda,
these metals have been converted to non-toxic form, which
is safe for internal use, and it could even not be possible to
recover metals from such preparations [41] . These trans-
formed forms of metals acts as carriers and catalysts, helping
the herbs to reach their desired site of action and also
increase their bioavailability. The proper dose and duration
of intake of these medicines are extremely important and
they should only be prescribed and taken under the
guidance of ayurvedic practitioners who are experts in this
particular field of medicine [42,112] .
The manufacture of many ayurvedic drugs in tablets or in
a capsule forms require fine grounding and processing
of crude herbs and its products. Particle sizes alter herbal
properties due the physical and chemical alterations in plant
compounds that occur during the blending, compression
and filling processes. Such dosage forms are not found to
be successful for ayurvedic products due to problems
encountered by therapeutic efficacy and compliance issues [4] .
However, these problems could be largely avoided when
single active molecules are developed from ayurvedic plant
products. Iwu, in his book Ethno-medicine as drug discovery ,
discussed the solubility issues in drugs discovery in detail
and these issues seem to be fit for ayurvedic drug products
as well. Although the active constituents predominantly
occur naturally as soluble salts or organic complexes with
solubility-enhancing matrices, the extraction processes often
lead to the dissociation of these organic compounds from
Ayurvedic drug discovery
1646 Expert Opin. Drug Discov. (2007) 2(12)
the water-soluble components, resulting in production of
insoluble extractives [43] . Meticulous experimentation or
customization of present drug delivery techniques would
help in handling some of the first-pass and bioavailability
issues with ayurvedic drug products.
13.4 Drugbotanical interactions
Plant product-based drug interactions are alarmingly rising
in countries where traditional plant medicines act as health-
care component (e.g., India and China) as well as in others
regions of the world where herbal supplemental drugs are
extensively used (e.g., US). The occurrences and reporting
on the drugbotanical interaction are also anticipated to
reach far more heights in the near future because of
the worldwide market for herbal medicine expecting to
reach a tune of $26 billion by the year 2011 [113] . Drug
interactions often result in pharmacokinetic (e.g., increased
clearance or reduced half-life) or pharmacodynamic altera-
tions (e.g., increased blood-clotting time or reduced glucose
levels) or, more frequently, in some level of both.
Drugbotanical interactions mainly occur because of herbal
components inducing or inhibiting (or acting as a substrate)
the drug-metabolizing cytochrome P450 (CYP) enzymes
(e.g., CYP3A4, CYP2D6, CYP2C9) and/or drug-transporting
proteins, such as P-glycoprotein, breast cancer resistance
protein and organic anion transporting peptides. Although
the predominant mechanisms of induction or inhibition are
thought to be due to modulation of the levels of the
transcription factors, such as pregnane-X-receptor and
constitutive androstane receptor that control the mRNA
expression levels of these genes, a number of other mecha-
nistic possibilities for drug interactions are only yet to be
discovered. Although plants products, such as St. Johns
Wort extract and grapefruit (or cranberry) juices are exten-
sively studied at the moment for their interactions [44,45] , the
majority of ayurvedic plant products are not yet completely
evaluated for their interaction with other prescription drugs.
Some of the well-assessed and available reports on drug
interactions with ayurvedic products are summarized in
Table 5 . Guggul or guggulipid, an antihyperlipidemic and
antiarthritis ayurvedic drug, is reported to interact with
azathiopurine, statins and a number of anticancer agents.
Laxative herbs (e.g., Aloe ) have been found to cause a serious
hypokalemic cardiac effect when co-administered with
potassium-lowering drugs. Bitter melon can induce severe
hypoglycemic effects when co-administered with other anti-
diabetic agents. For some plant compounds, the constituents
and the proportions of those constituents, depending on
the type and form of plant products administered, largely
determine the presence or the extent of the interaction.
For example, garlic ( Allium sativum ) is commonly used
as dehyd rated garlic powder, garlic oil or aged garlic
preparations. Although dehydrated garlic powder contains
two main groups of organo-sulfur constituents, that is,
S -alkylcysteine (mostly allicin) and -glutamyl- S -alkylcyteines,
the -glutamyl- S -alkylcyteines are completely hydrolyzed to
mainly S -allylcysteine and S -1-propenylcysteine with no
presence of volatile sulfides in aged garlic preparation.
Allicin, the major active component in garlic, is also converted
to a concentrate of allylic mono-, di- and tri-sulfides in
dispersed oil during steam-distillation process of garlic oil
generation. Allicin is also the major ingredient responsible
for lowering blood cholesterol levels that possibly inhibits
key enzymatic reactions in the cholesterol biosynthetic
pathway. Depending on the form of garlic preparation, the
extent and magnitude of cholesterol-lowering effects of
garlic products would vary distinctly to a measurable extent.
Garlic powder and aged garlic are also known to have
antithrombolytic activity that may contribute to additional
cardiovascular effects. Earlier clinical studies on garlic
supplements and HIV-1 protease inhibitors (saquinavir)
showed distinct pharmacokinetic alterations and CYP3A
involvement [46] , whereas other follow-up studies with
different CYP3A substrates (midazolam, alprazolam) did not
show any CYP3A-based drug interactions [47,48] . This
suggests multiple factors including the form of garlic supple-
ments and substrate dependence in interaction with CYP3A
might be important in understanding garlic-based drug
interaction. Garlic products have also been shown to signifi-
cantly decrease CYP2E1 activity [47] , but not CYP2D6 and
CYP1A2 activities [48] . Although the content of active
components in herbal extracts with respect to both composi-
tion and uniformity is a major issue in understanding
drugherb interactions, patient compliance and other related
issues also creates distinct challenges in managing drugherb
interactions. Missing reports or misreports of patients usage
of herbal products to their healthcare providers, significant
lack of prospective studies available with plant products
especially in a disease context (as opposed to studies in
healthy volunteers), lack of governmental regulations
resulting in large variation in the quality of commercial
products and magnitudes of herbdrug interactions as well
as inability to extrapolate or predict results from one
herbal product to another, still remain prominent issues
to address.
14. Ayurvedic drug development in India:
government and private sectors
The Indian government agencies, such as the Department of
Biotechnology, the Ministry of Health and Family Welfare,
ICMR and CSIR, have brought significant initiatives for
ayurvedic drug discovery and development. The Department
of Biotechnology initiated the network program on
bio-prospecting of biological wealth using biotechnological
tools and this includes bio-prospecting of molecules and
genes for product development. As mentioned earlier,
the CSIR and the ICMR have successfully implemented
a reverse-pharmacology approach in many of their drug
discovery processes. The CSIR has adopted this new path
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1647
through the New Millenium Indian Leadership Initiative
and this team has a network of 19 CSIR laboratories
along with several research and development institutions,
as a multi-disciplinary approach. It is aimed at studying
and researching various diseases, such as diabetes, arthritis
and hepatitis, paving the way for new hits and leads.
The government of India has framed good manufacturing
practice regulations to improve the standard and quality of
manufactured ayurvedic drugs. New rules delineating the
essential infrastructure, manpower and quality-control
requirements came into force during the year 2000 and
reinforced as part of the Drugs and Cosmetics act of
1940 [49] . As a result, ayurvedic medicine-manufacturing
firms are obligated to comply with these rules and use
only the ingredients from the recommended resource
materials. For any type of newer formulations, documented
safety and efficacy data are necessitated for further develop-
ment as a drug product [50] . An exclusive department
called AYUSH was also established by the Indian govern-
ment in 1995 to specifically promote the indigenous
medicinal system. Prioritized areas include standardization
of drugs, enhancement of availability of raw materials,
research and development, information communication,
education and awareness as well as larger involvement of
the national system in delivering healthcare. The Indian
government also established several new laboratories exclu-
sively for traditional Indian medicine drug testing, and
is preesemtly upgrading existing laboratories to test
herbal medicines for safety and quality requirements for
licensing purposes [50] . To protect the intellectual property
rights of ayurvedic drugs, the Ministry of Health and Family
Welfare has also established a traditional-knowledge
digital library that will particularly aid in traditional
knowledge resource classification (TKRC) [51] . The TKRC is
similar to and in accordance with the international patent
classification system that acts as a bridge between the
ayurvedic knowledge and patent examiners. This would
promote accuracies in granting research patents on ayurvedic
drug formulations [50] .
Private pharmaceutical companies in India have also
immensely renewed their interest in favor of ayurvedic
drug discovery and development. Indian pharmaceutical
companies, such as Himalaya Drug Company (HDC),
Emami, Aswini, Ayur, Dabur India Limited and Cholayil
Pharma, have already patented many of their herbal and
ayurvedic products both in India and others parts of
the world. The ayurvedic products manufactured by HDC
are exported to as many as 60 countries all over the world
and its herbal laxative preparation has been recently
patented in the US. HDCs ayurvedic products are also
registered as a pharmaceutical specialty in many countries
(e.g., Switzerland). Dabur India Limited, considered as
one of the leading Indian pharmaceutical companies, owns
about 30 patents in the US alone. It is also one of the
only two pharmaceutical companies in the world to
introduce Paclitaxel, an anticancer drug. Daburs research
foundation also possesses the infrastructure for unique
eco-friendly drug extracting and processing procedures
from plant resources. Zandu Indian Pharmaceuticals
manufactures about 300 health-promoting ayurveda-based
products using hundreds of medicinal herbs and
herb extracts [114] .
Table 5 . Ayurvedic herbdrug interactions.
Ayurvedic medicine Drugs Symptoms of interactions
Evolvulus alsinoides [79]
(Shankhapushpi syrup)
Phenytoin Co-administration reduces anti-epileptic activity
and serum levels of phenytoin
Withanolides from Withania somnifera [80] Digoxin assay Falsely lowers digoxin values with MEIA assay
Guggul lipid from Commiphora mukul [115] Aspirin Increase the activity of aspirin leading to
bleeding problems
Areca catechu [81] Prednisone and salbutamol Inadequate control of asthma
Allium sativum [82] Warfarin Increased INR
Momoridica charantia [83] Chlorpropamide Less glucosuria
Glycyrrhiza glabra [84] Prednisolone Increase plasma concentrations
Tamarindus indica [85] Aspirin Increase availability of aspirin
Trigonella foenum-graecum
(Fenugreek) [86]
Warfarin Increased INR
Camellia sinensis (Green tea) [87] Warfarin Increased INR
Foeniculum vulgare (Fennel) [88] Enalapril Cough suppression
Zingiber ofcinale (Ginger) [89] NSAIDS No effect of NSAIDS
Citrus paradisi (Grapefruit juice) [90] Fluoxedine and trazodone Serotonin syndrome
INR: International normalized ratio; MEIA: Microparticle enzyme immunoassay; NSAID: Nonsteroidal anti-inammatory drug.
Ayurvedic drug discovery
1648 Expert Opin. Drug Discov. (2007) 2(12)
Despite significant strides in herbal pharmaceuticals,
Indias present share is only of $1 billion out
of US$62 billion in the global herbal market (< 2% of
the global market share), ranking only in the third position.
China seems to do better than India by holding 30%
of the global herbal market share, ranking second overall.
However, it is widely considered that a huge opportunity
is still awaiting the Indian pharmaceutical companies and
institutions by way of new innovations, patents and
trademarks. Incorporation of modern pharmaceutical,
biotechnological and chemical tools is firmly believed to
bring a new leverage in ayurvedic drug discovery by way of
fusion of traditional and modern medicines [114] .
15. Conclusion
The mechanistic basis of action of medicinal herbs used in
ayurvedic Indian medicine, especially in the context of
understanding disease processes in molecular terms, is pav-
ing the way for identifying new drug compounds as well as
new drug targets. At the same time, the present and increased
prevalence of diseases that are not completely amenable to
therapeutic control by modern medicines is creating a surge
in the interest of pharmaceutical companies in developing
new solutions from therapeutic principles put forth by tradi-
tional medicines. These trends suggest that drug discovery
efforts from natural products and specifically from those
described in traditional medicines, will undoubtedly offer
more significant drug leads for future development. This
review presents ayurvedic drug discovery approaches
suggested by ayurvedic experts in the context of new drug
discovery as well as the practical challenges connecting
traditional ayurvedic resources to present drug discovery
methodologies. Conformation of ayurvedic drug discovery
to modern drug standards and regulations requires signifi-
cant customization and up-scaling efforts besides the stan-
dardized drug discovery steps. Careful evaluation of ayurvedic
herbs and herb products in accordance to present-day
practice of drug evaluation and pre-clinical trials is
anticipated to bring more successful therapeutic outcomes to
the worlds medicine.
16. Expert opinion
Ayurvedic drugs are used by Indian populations as
mainstream, alternative, complementary or integrative forms
of medicines. Several joint-ventures of western and ayurvedic
medical specialty centers are successfully being initiated in
India (e.g., Mohans diabetes specialty center and Arya
Vaidyas pharmacy in Chennai) to offer multimodal
treatment options incorporating advantages put forth by
both medical streams. Moreover, it is also common to notice
medical practitioners suggesting the incorporation of natural
medicine-based procedures and medications in the regularly
prescribed modern drugs to handle disorders such as
diabetes, jaundice, renal failure, chicken pox, herpes
viral infections etc. Furthermore, multiherbal ayurvedic
formulatory drugs have been clearly identified to possess
much lesser side effects or toxicities compared with the
modern drug-based monotherapy used in treating diseases
such as cancer. Despite much of its clinical success in
developing countries, there is a significant backlog in
the standardized ayurvedic drug discovery efforts to go
beyond what has slowly emerged so far. Furthermore, as
the global use of ayurvedic knowledge is strikingly
minimal, ayurvedic medicine is still stigmatized as one of
the unconventional forms of medicine in many parts of
the world.
Ayurvedic drug discovery incorporating modern trends in
compound identification and clinical screening would help
in the widespread use of ayurvedic drugs, uncovering
potentials and benefits described in ayurvedic classics. In
order to successfully compete for a significant stake in
the global market, there is a pressing need for ayurvedic
practitioners and scientists to systematically evaluate the
therapeutic potentials of ayurvedic products as per standard-
ized regulations (e.g., World Health Organization guide-
lines). Although the word systematic research may inspire
images of large and expensive clinical trials, case-study trials
suggested by the Office of Alternative Medicine at the
NIH [40] is a simplistic research design with a multitude of
advantages. It is less expensive and particularly suited
for ayurvedic practitioners in a smaller clinical setting.
The essential elements include maintenance of records of
diagnosis, pre-treatment and examination schedules, docu-
mentation of treatment details including clinical status of
the patients, documentation of clinical observations includ-
ing side effects and drug responses and inter-individual
variations in treatment responses. These studies form the
initial basis for reverse-pharmacology approaches in drug
discovery and provide valuable contributions to the existing
body of knowledge on a given subject of interest. In
addition to triggering new drug discovery interests, further
standardizations, dose determinations, toxicity profile
identifications and quality-control measurements will
also help to identify safe and effective ayurvedic drugs
and formulations.
Ayurvedic extract libraries and resources for drug
screening procedures can tremendously favor novel
drug identification. In particular, high demand exists for
alternative-medicines in treating chronic and degenerative
type of ailments (e.g., Alzheimers disease, rheumatoid
arthritis). Although recent genomic understanding provides
a better picture on the biological targets for ayurvedic
drug products, recategorizing ayurvedic herbs and products
based on the current molecular understanding of disease
processes would highly facilitate a focused search for
new drug leads. This, along with substantial inputs in
terms of innovation, customization, infrastructure and
technology, would clearly facilitate standardized drug
Balachandran & Govindarajan
Expert Opin. Drug Discov. (2007) 2(12) 1649
discovery procedures from ayurvedic resources. Critical
challenges described earlier, but not limited to, are required
to be meticulously addressed for productive outcomes in
ayurvedic drug discovery. Although this is the case for
well-studied ayurvedic plants, rigorous scientific experimen-
tations are still required for a number of other medicinal
herbs for which understanding on their biochemical basis
of cellular action remains less understood. Considering
these major issues and bringing specializations from
different streams under one roof, ayurvedic drug
discovery could be pushed forward to shed light on novel
therapeutic interventions.
Acknowledgements
The authors would like to thank Li Liu, Department of
Pharmaceutics, University of Washington, for her critical
comments on the manuscript.
Declaration of interest
The authors state no conflict of interest and have received
no payment in preparation of this manuscript. The views
and opinions expressed in this article are those of the authors
only and not necessarily of the organizations they work for.
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Afliation
Premalatha Balachandran


1
PhD &
Rajgopal Govindarajan
2
PhD

Author for correspondence

1
University of Mississippi,
National Center for Natural Products Research,
Research Institute of Pharmaceutical Sciences,
School of Pharmacy,
MS 38677, USA
Tel: +1 662 915 3463 ; Fax: +1 662 915 7062 ;
E-mail: prembala@olemiss.edu

2
University of Washington,
Department of Pharmaceutics,
School of Pharmacy,
Seattle, WA 98195, USA

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