1. INTRODUCTION

1.1. Natural Products in Traditional Medicines

Usage of natural entities from plants, animals and mineral sources in

diagnosis, prophylaxis and therapy of human ailments and for invigoration of

body systems is as old as human civilization1. Plants were strongly believed to

have miraculous healing power in almost all ancient civilizations. Because

Homo sapiens are herbivores to some degree, they first encountered bioactive

agents in vegetable food items2. Having lived harmoniously in close association

with the environment, humans learned to utilize the toxic and medicinal

properties of natural products. Some of those toxic plants were used as poisons

for causing death as arrow poisons for hunting foods, warfare, depredating wild

animals and for gaining mastery over a hostile environment3. The most

remarkable of all the ancient inventions was the art of utilizing these toxic and

medicinal natural products for treating various ailments but the ethno –

medical knowledge was restricted to a few elites such as priests, medicine men,

shamans, magicians and witch doctors2. Although some cultures use

individual herbs as medicines, many traditions propounded powerful

combinations with different ingredients known as poultices, tinctures and

mixtures.

It was the Mesopotamians who first used the herbs like oils of cypress,

cedar, liquorice and poppy juice for treating different ailments in 2600 BC,

followed by the Indian Buddhist system of medicine that dates back to 2500

BC2.

The earliest records of utility of plants were found in Babylon circa 1770

BC in the code of Hammurabi and in ancient Egypt circa 1550 BC. Ancient

Egyptians believed medicinal plants have utility even in the afterlife of their

pharaohs. Many plants have been recovered from the Giza pyramids and can

be found on display in a dark corner of Access Excellence Resource Center he

Cairo Museum3.

The Egyptian’s Ebers Papyrus (1500 BC) documented seven hundred

drugs including formulae for gargles, snuffs, poultices, infusions, pills and

ointments5. The Chinese material medica Wu-Shi Er-Bing Fang contains 52

prescriptions in 1100 BC6.

Ayurveda, the ancient healing system of India flourished in the Vedic era

in India. In its classical texts Charaka Samhita and Sushruta Samhita were

written around 1000 B.C documented the medicinal use of plants like Datura,

Aconitum, Cannabis and Sarcostemma2. The Ayurvedic Materia Medica includes

600 medicinal plants along with its therapeutics. Herbs like turmeric,

fenugreek, ginger, garlic and holy basil were integral parts of Ayurvedic as

mono and polyherbal formulations.

From these ancient cultures, some of the knowledge reached

Mediterranean countries through traders and migrants and it was in

Hippocrates’s (460 – 377 BC) time that pharmacognosy reached a summit in

Greece2. Theophrastus (300 to 322 BC) who was the Philosopher and

Naturalist was the first to deal with the history of plants, which later on helped

in the classification of plants including herbs. Pedanius Dioscorides, a Greek

Physician, produced De material medica in 78 AD, which describes more than

500 medicinal plants and their uses in detail.

Galen (129 – 199 AD) founded “Galenics” and taught Pharmacy and

Medicine in Rome. Avicenna (980 – 1037 AD), a Persian pharmacist, physician,

philosopher and a poet described 1400 drugs and medicinal plants which

greatly contributed in the formation of a codified Graeco – Roman Medicine in

5th century7. Paracelsus (1493 – 1541) administered dosage formulations

separating “Arkanum” for non-active ingredients of drugs. Western medicine

and Pharmacy originated from this medicinal system. Tibetan medicine, also

called Gso – ba Rig-pa, took shape in the 7th to 8th century with the advent of

Mahayana Buddhism in the country8. Bhutanese traditional medicine known

as Gso – ba Rig-pa was conceived subsequent to Tibetian medicine in the 8th

century contains more than 300 herbal formularies and recipes9. In the USA,

Homeopathy, that includes hydrotherapy, nutritional therapy, herbal therapy,

manual manipulation and midwifery, was founded by German physician

Hahnemann (1755 – 1843)

1.2. Potential of Natural Products:

With the brisk progress in various fields of human activity, the field of

medicine and its allied sciences has also made rapid strides. The synthesis of

many chemicals and their introduction into therapeutics as drugs certainly

revolutionized the treatment of diseases. Today we have a large number of

synthetic drugs that are efficient against many diseases.

When there is a surfeit of such established drugs, it may look a little bit

odd if one tries to go back to indigenous drugs and bring out new remedies.

The scientists of synthetic drugs will be the strongest critics of such a progress.

Though one may not rancor the pride of place given to synthetic drugs, it is the

known fact that these drugs are not fully un harmful to us. They produce a

large array of adverse reactions and have been the cause of a number of

diseases. Another consideration should be the cost factor. Many of the

synthetic drugs are expensive for the common man. It is natural that under

these conditions, to understand the motives behind a person’s interest in the

field of natural products and the drugs obtained from the rich flora and fauna

of this ancient land2.

Nature has an enormous diversity of chemical compounds as secondary

metabolites, which are considered to be waste products, but involved in the

relationship of the organism with the environment9, 10. The necessary features

required for the biological relevance is fulfilled by natural products as they

have evolved to interact with multiple proteins and can be regarded as

embodying privileged structures. Privileged structures are compound classes

that can bind to various proteinaceous receptors. They are synthesized and

modified by more than one protein and hence they often display multiple

biological activities mediated by interaction with different proteins.

The claims of therapeutic efficiency and lack of toxicity of many plants

have been scientifically proved in recent years. However, there is immense

number of plants of questionable value among the enormous repertory of

indigenous drugs. It will be a worthy exercise if one tries to select the best out

of them. There are large numbers of plants, which have to be examined

thoroughly for useful activity or lack of it.

1.3. Natural Products Derived from Medicinal Plants:

The ethnobotany and ubiquitous plants provide rich source for natural

drug research and development. In recent years, the use of information about

traditional medicinal plant research has again received substantial interest.

But it was not until the 19th century that human began to isolate the active

principles of medicinal plants and the historic discovery of quinine from

cinchona bark was made by the French scientists Caventou and Pelletier7. A

brief review of some important active principles isolated so far from plant

species has been given in Table: 1.1.

Table: 1.1: Phytochemicals used as drugs from plant source4,5.

Biological Source Chemical

Constitutents

Medicinal Uses

Adonis vernalis Adoniside Cardiotonic

Agrimonia supatoria Agrimophol Anthelmintic

Ammi visnaga Kheltin Bronchodilator

Anamirta cocculus Picrotoxin Analeptic

Ananas comosus Bromelain Anti-inflammatory

Andrographis paniculata

Andrographolide, Neoandrographolide

Bacillary dysentery

Anisodus tanguticus Anisodine Anticholinergic

Ardisia japonica Bergenin Antitussive

Areca catechu Arecoline Anthelmintic

Artemisia maritima Santonin Ascaricide

Atropa belladonna Atropine Anticholinergic

Berberis vulgaris Berberine Bacillary dysentery

Betula alba Betulinic acid Anticancer

Brassica nigra Allylisothiocyanate Rubefacient

Camellia sinensis Caffeine CNS stimulant

Camptotheca acuminata

Irinotecan, Topotecan Anticancer

Cannabis sativa Tetrahydrocannabinol Antiemetic

Carica papaya Chymopapain, Papain Proteolytic

Cassia species Danthron, Sennoside A, B

Laxative

Catharanthus roseus Vinblastine Antitumor

Catharanthus roseus Vincristine Antitumor

Centella asiatica Asiaticoside Vulnerary

Cephaelis ipecacuanha Emetine Amoebicide, emetic

Chondrodendron tomentosum

Tubocurarine Skeletal muscle

Relaxant

Cinchona ledgeriana Quinidine, Quinine Antimalarial, Antiarrhythmic,

Antipyretic

Cinnamomum camphora

Camphor Rubefacient

Cissampelos pareira Cissampeline Skeletal muscle

Relaxant

Citrus species Hesperidin, Rutin Capillary fragility

Convallaria majalis Convallatoxin Cardiotonic

Coptis japonica Palmatin Antipyretic

Corydalis ambigua Tetrahydropalmatine Analgesic,sedative

Crotalaria sessiliflora Monocrotaline Antitumor

Curcuma longa Curcumin Choleretic

Cynara scolymus Cynarin Choleretic

Cytisus scoparius Sparteine Oxytocic

Datura species Scopolamine Sedative

Digenea simplex Kaibic acid Ascaricide

Digitalis lanata Acetyldigoxin, Deslanoside,

Lanatoside A, B, C

Cardiotonic

Digitalis purpurea Digitalin,Digitoxin,

Digoxin

Cardiotonic

Ephedra sinica Ephedrine,

Pseudoephedrine

Sympathomimetic,

antihistamine

Erythroxylon coca Cocaine Local anesthetic

Gaultheria procumbens Methyl salicylate Rubefacient

Glaucium flavum Glaucine Antitussive

Glycyrrhiza glabra Glycyrrhizin Sweetener

Gossypium species Gossypol Male contraceptive

Hemsleya amabilis Hemsleyadin Bacillary dysentery

Hydrangea macrophylla

Phyllodulcin Sweetener

Hydrastis Canadensis Hydrastine Haemostatic,

astringent

Hyoscyamus niger Hyoscyamine Anticholinergic

Larrea divaricata Nordihydroguaiaretic acid

Antioxidant

Lobelia inflata Lobeline Smoking deterrant, respiratory stimulant

Lonchocarpus nicou Rotenone Piscicide, insecticide

Mentha species Menthol Rubefacient

Mucuna species l-dopa Antiparkinsonism

Nicotiana tabacum Nicotine Insecticide

Ocotea glaziovii Glasiovine Antidepressant

Papaver somniferum Codeine,Morphine,

Noscapine

Analgesic,antitussi

ve, Smooth muscle relaxant

Pausinystalia yohimbe Yohimbine Aphrodisiac

Physostigma venenosum

Physostigmine Cholinesterase

Inhibitor

Piper methysticum Kawain Tranquillizer

Podophyllum peltatum Podophyllotoxin, Teniposide

Anticancer,

Antitumor

Quisqualis indica qualsqualic acid Anthelmintic

Rauwolfia canescens Deserpidine Antihypertensive,

tranquillizer

Rauwolfia serpentina Ajmalicine,

Rescinnamine, Reserpine

Circulatory

Disorders

Rhododendron molle Rhomitoxin Antihypertensive

Rorippa indica Rorifone Antitussive

Salix alba Salicin Analgesic

Silybum marianum Silymarin Antihepatotoxic

Sophora pschycarpa Pachycarpine Oxytocic

Stephania sinica Rotundine Analgesic,sedative

Stephania tetrantra Tetrandrine Antihypertensive

Stevia rebaudiana Stevioside Sweetener

Strophanthus gratus Ouabain Cardiotonic

Strychnos nux-vomica Strychnine CNS stimulant

Tabebuia species Lapachol Anticancer

Taxus brevifolia Taxol Antitumor

Thymus vulgaris Thymol Antifungal

Trichosanthes kirilowii Trichosanthin Abortifacient

Urginea maritima Scillaren A Cardiotonic

Valeriana officinalis Valapotriates Sedative

Veratrum album Protoveratrine A, B Antihypertensive

Vinca minor Vasicine Cerebral stimulant

Some of the prominent commercial plant-derived medicinal compounds

include: Arteether, Galantamine, Nitisinone, Colchicine, Betulinic acid,

Camptothecin, Topotecan, 9-aminocamptothecin, Delta-9-

tetrahydrocannabinol, Betalapachone, Etoposide, Lapachol, Podophyllotoxin,

pilocarpine, Podophyllinic acid, Vinblastine, Vincristine, Vindesine,

scopolamine, Vinorelbine, Docetaxel, Paclitaxel and Tubocurarine11.

Podophyllotoxins isolated from Podophyllum species did not prove

satisfactory against treatment of cancer in clinical trials due to side effects.

Structure activity studies to modify Podophyllotoxin resulted in two compounds

designated etoposide and tenoposide clinically effective in the treatment of lung

cancer31.

A new synthetic Vinca alkaloid designated navelbine has shown

significant anti tumor effect against p-388 leukemia resistant to the vincristine

cell line p-377-VCR. The compound has low toxicity and it can be tolerated in

high doses12.

Taxol has been isolated from several species of the genus taxus such as

Taxus brevefolia, Taxus baccata, taxus cuspidata and it is complex diterpenoid

derivative possessing a rare oxetane ring. It exhibited antineoplastic antimitotic

properties which are under exploitation for the treatment of cancer. The allylic

hydroxyl ester function is responsible for the activity of taxol13.

Arteether is a potent antimalarial drug from artemisinin, a sesquiterpene

lactones isolated from Artemisia annua Linn. The Plant is used in traditional

Chinese system14.

Galantamine isolated from Galanthus woronowii is approved for the

treatment of Alzheimer’s disease15.

Curcumin isolated from rhizomes of Curcuma longa proved promising as

anti-inflammatory agents without side effects commonly encountered with the

NSAIDS16.

1.4. Natural products as lead molecules in drug discovery

Natural products have been proven templates for the development of new

drugs17. Several methods have been utilized to acquire compounds for drug

discovery including isolation from plants and other sources like, synthetic

chemistry, combinatorial chemistry, and molecular modeling18,19,20. Despite the

recent curiosity in molecular modeling, combinatorial chemistry and other

synthetic chemistry techniques, natural products and particularly medicinal

plants remain important sources of new drugs, new drug leads, and new

chemical entities21,22. In 2001 and 2002, about one quarter of the best selling

drugs worldwide were from natural products or its derivatives.

The drug discovery from plants is both multi-disciplinary and inter-

disciplinary. It commences with a botanist, ethnobotanist, ethno-

pharmacologist, or plant ecologist who collects and identified the plants of

interest. Phytochemists prepare the extracts from the plant materials and

subject these extracts to biological screening in bioassays and commence the

process of isolation and characterization of the active compounds through

bioassay-directed fractionations. Moreover, molecular biologist has become

essential as they determine and implement the screening assays relevant to

molecular targets. The second step in the drug discovery process is lead

optimization (involving medicinal and combinatorial chemistry), lead

development (including toxicology, pharmacology, pharmacokinetics, and drug

delivery) and clinical trials.

Different approaches to drug discovery from plants can be enumerated as

Random selection followed by chemical screening,

Random selection followed by one or more biological assays,

Follow-up of biological activity reports,

Follow-up of ethnomedical (traditional medicine) use of plants,

Use of appropriate plant parts as such in powdered from or preparation of

enriched/standardized extracts (herbal product development)

Use of a plant product, biologically potent but inundated with other

issues, as a lead for further chemistry, and subsequent development of single

new compounds as drugs21.

The significant vision of drug discovery process from plants is merging

the knowledge of traditional systems such as Ayurvedic with the dramatic

power of combinatorial sciences and high throughput screening (HTS). It will

help in the initiation of structure activity libraries. Ayurveda knowledge and

experimental database can provide new efficient leads to reduce time, money

and toxicity, which are the three main hurdles in drug development. These

records are particularly valuable, since these medicines have been tested and

most of the tested drugs proved effective for thousands of people23.

Globally, there is a positive trend towards health, integrative sciences,

systems biology approaches in drug discovery and therapeutics that has

remained one of the unique features of ayurveda24. A golden triangle consisting

of ayurveda, modern medicine and science will converge to form a real

discovery engine that can result in newer, safer, cheaper and effective

therapies.

1.5. Challenges in herbal research:

In spite of the success of drug discovery programmes from plant in the

past 2-3 decades, future endeavours face many challenges. Natural product

scientists and pharmaceutical industries will need to improve continuously the

quality and quantity of compounds that enter the drug development phase to

keep pace with the other drug discovery efforts. The process of drug discovery

has been estimated to take an average period of 10 years and cost more than

800 million dollars. Much of this time and money is spent on the numerous

leads that are discarded during the drug discovery process25.

The progress of herbal drug development is associated with numerous

problems. Crude herbs/plants are mostly formulated as tablet and capsule and

to some extent as oral liquid preparations. These dosage forms are not

successful due to problems such as absorption, therapeutic efficacy and poor

compliance. Tablet or capsule dosage forms necessitate powdering of crude

herbs and particle size affects the process of blending, compression and filling.

Further, homogeneity is tricky to accomplish due to the handling of large bulk

quantities, high moisture content and inherent nature of raw materials (crude

drug). Crude extracts are difficult to formulate in solid dosage forms due to

their hygroscopic nature, poor solubility and stickiness21.

As drug discovery from plants has traditionally been time-consuming,

faster and better methods for plant collection, bioassay screening, compound

isolation and compound development must be employed. The design,

determination and implementation of appropriate, clinically relevant, high-

throughput bioassays are difficult processes for all drug discovery

programmes26,27. Although the design of high-throughput screening assays can

be challenging28, once a screening assay is in place, compound and extract

libraries can be tested for biological activity. Screening of extract libraries is

often problematic, due to poor solubility, but new techniques including pre-

fractionation of extracts can alleviate some of these issues29.

Challenges in bioassay screening remain an important issue in the

future of drug discovery from medicinal plants. The speed of active compound

isolation can be increased using hyphenated techniques like NMR and LC-MS.

Development of drugs from lead compounds which are isolated from plants face

unique challenges. Natural products, in general, are typically isolated in

minute quantities that are insufficient for lead optimization, lead development

and clinical trials. Thus, there is a necessity to develop collaboration with

synthetic and medicinal chemists to explore the possibilities of its semi-

synthesis or total synthesis30. One can improve the natural products

development by generating natural products libraries that combine the features

of natural products with combinatorial chemistry. Even with all the challenges

facing drug discovery from medicinal plants, natural products isolated from

medicinal plants can be predicted to remain as essential component in the

search for new medicines31.

1.6. Structural elucidation of natural products in discovery of lead

molecule:

The chemical structures of natural products are tremendously diverse.

Such diversity can present a challenge to the analytical or medicinal chemist

attempting to unravel the mystery of the chemical structure of an unknown

material presented to him. However, modern technology has made structure

identification simpler and faster. Today, scientists utilize such

techniques such as MS, IR, and Fourier transform infrared spectroscopy

(FTIR), NMR, Fourier transform nuclear magnetic resonance spectroscopy

(FTNMR) and others for structural elucidation.

1.7. Bioassays as potential tool in herbal drug research32:

In any natural product isolation program in which the end product is to

be a drug or a lead compound, some type of bioassay screening or

pharmacological evaluation must be necessarily used to guide the isolation

towards the pure bioactive compound. The biomass is collected, dried, and

extracted in to a suitable solvent to give an extract, which is then screened for

bioactivity. Bioassays (BA) could involve the use of in-vivo systems (e.g. clinical

trials, whole animal experiments), ex-vivo systems (e.g. isolated tissues and

organs) and in-vitro systems (e.g. cultured cells). Often BA are linked to the

process of fractionation and isolation, known as bioassay-guided fractionation,

in which chromatographic techniques are used to separate the extract into its

individual components, the biological activity is checked at all stages until a

pure active compound is obtained33.

As these are non selective and indicate whether or not a certain

extract/compound is active, active compounds from such assays (Biomarkers)

can later be subjected to specialized assays.

Hippocratic screening uses intact animals and involves the effect of plant

extracts or their derivatives on gross behaviour of animals.

Brine shrimp lethality test involves testing lethality to brine shrimp

nauplii recommended for screening of plants for general bioactivity.

These are specialized BA and yield information on specific bioactivity and

could be used as secondary assays for fraction showing activity in the general

BA. These assays may either use lower organisms, cellular/sub cellular

systems, enzymes, intact cells or isolated organs.

E.g:

Assay Pharmacological Significance

Trypsin inhibition Anti-inflammatory, Antiviral

DPPH scavenging Antioxidant

Antimicrobial Infectious conditions

Amylase inhibition Obesity, diabetes

Monoamine oxidase Hypertension, Depression

Utilize intact cells of human or animal origin to detect various

bioactivities like antidiabetic, hepatoprotective, immunomodulatory,

antiinflammatory and analgesic activities etc.

1.8. Bioassays in primary screening:

These are relatively simple, with the main objective to discover large

number of bioactive molecules in the lab itself. e.g. Brine shrimp lethality test,

antibacterial tests, crown gall tumour inhibition test.

Physical methods of analysis like chromatography are of limited use,

since they can be used to detect/quantify a selected group of compounds. By

utilizing in-vitro BA, extracts can be tested as a whole and the biological

response can be expressed as ED50, LD50 etc. (quantal response) with 95%

confidence interval. Deviation from the standard values can be an indication

for inadequate quality. Also, when an extract is tested in a BA, both the known

and unknown bioactive express their effect to influence the assay results.

However in a chemical assay only the known bioactive can be assayed; the

unknown ones are generally ignored.

In-vivo studies are relevant to clinical conditions and also provide toxicity

data, but costs, complex designs, difficulties in determining mode of action are

among some of their disadvantages. In-vitro studies on the other hand are

faster and use relatively small amounts of materials. The pharmacological

evaluation of extracts and pure isolated compounds is an essential aspect of

drug discovery process and development in the area of in-vitro techniques has

substantially transformed this facet of natural product chemistry.

1.9. The recent re-emergence of plant remedies34:

The factors that are responsible for recent resurgence of plant remedies

are

The pharmacological effects of plant medicines

The side effects of modern drugs

The development of Science and Technology

The discovery of antibiotics and vaccines in the 20th century dramatically

changed medical practice worldwide and as a result a separate field of

ethnomedicine emerged as an academic specialization focusing on traditional

healing systems3. The investigation of the principles of drug action at the

molecular level in Japanese traditional Sino – medicine had resulted in

obtaining many novel compounds and the uncovering of new mechanisms of

drug action7. Clinical trials of Tibetan medicine, the PADMA Products, also

proved successful in the treatment of irritable bowel syndrome and fibrinolysis

with stable intermittent claudication3. These products also furnished new

oxidative mechanisms at the molecular level9. Thus, traditional medicines were

found to be effectively addressing the health needs of millions of people

including developed nations by completely different strategies and well-defined

approaches and generally with minimal side effects35. Current WHO estimates

show that 75% of the French population, 30% of the Vietnamese population

and 40% of Indonesia’s population use traditional medicines17. In Germany

77% of pain clinics provide acupuncture, in Japan 72% of registered western

style Doctors use kampo medicine and in Bhutan, traditional medicine caters

to 80% of the population17. Overall traditional medicines provide primary

health care needs to almost 65 to 85% of the world’s population including

developed nations35.

In terms of economic value, traditional therapies contribute to US dollars

60 billion a year and the USA alone spends US dollars 2.7 billion per year

followed by china with US dollars 1.8 billion and Australia with Australian

dollar one billion a year9. Since almost every traditional medicine regimen uses

medicinal plants as the bulk ingredients, they also play significant roles in

natural product based drug discoveries. More than 13,000 species of plants are

used in traditional medicines and herbal cosmetics35. About 8,000 of these

medicinal plant species are known in South Asia alone36. Many pharmaceutical

companies have successfully explored these medicinal plants by applying an

ethno – directed bio rational approach2. In fact, among the search strategies,

the ethno – directed bio – rational approach has proved to be the shortest and

the most effective search strategy for discovering drugs from nature. In survey

conducted, out of 800 medicinal plant extracts collected from Vietnam and

Laos, at least 25 biologically active compounds were isolated; of these 13 were

new anti – HIV agents and 3 were anti-malarial agents2. Similarly, in the USA,

out of 119 plant drugs available from 1959 to 1980, 74% of these were

discovered as a result of chemical studies directed at isolating the active

substances from the plants used in traditional medicines8.

However, in using this ethno directed search strategy, it is crucial to

have intimate understanding of the disease concepts of the culture whose

Pharmacopeia is under examination. The products used as medicines by local

people are usually not those that are tested in the laboratory. Most of the

effective brews or formularies are multi ingredient compounds. Chemical

reactions occur within these mixtures or poultices and are most often

associated with synergism making them more effective than the single isolated

lead compound. When the medicinal plants are subjected to phytochemical

screening, researchers often target only one compound, or a few limited

compounds, which quite often turn out to be biologically inactive owing to the

loss of other active components during the screening process. Therefore the

ethanomedical indication may not necessarily be productive when screening is

directed towards only specific phytochemical isolation.

Medicinal herbs are considered to be chemical factories as they contain

multitude of chemical compounds like alkaloids, glycosides, saponins, resins,

oleoresins, sesquiterpene lactones and oils (essential and fixed). Today there is

growing interest in chemical composition of plant based medicines. Several

bioactive constituents have been isolated and studied for pharmacological

activity. In the commercial market, medicinal herbs are used as raw drugs,

extracts, tinctures or dosage forms. Further, the isolated active constituents

are used for applied research. By understanding the biochemical pathways of

its production, it helps the medicinal chemists to derive the possible routes of

synthesis in large scale either by utilizing its starting materials or its

intermediates. Because of this reason, in the last few decades, phyto chemistry

(study of plants) has been making rapid progress and herbal products are

becoming popular.

In the modern scenario, Phyto chemistry based research is attracting

more and more attention of the modern pharmaceutical industries, as scientist

has become aware and interest that herbs have almost infinite resources for

medicine development. Over 2,48,000 species of higher plants have been

botanically identified and from these 12,000 plants are known to have

medicinal properties. However, less than 10% of all plants have been

investigated in the phyto chemical and pharmacological point of view26,37. From

this small percentage, innumerable therapeutically indispensable compounds

have been isolated.

Herbal medicine is a major drug component and an integral part of the

culture and civilization. In modern society, herbal medicine based on the

heritage continues to flourish and play an indispensable role in the current

healthcare and well-being of millions of people. Peoples of developing countries

are becoming disillusioned with modern health care and are seeking an

alternative therapy (Kong et al., 2003). Traditional or complementary medicine

has seen an upsurge in recent years and according to two surveys, 48.5%

Australian respondents, and 34% of American respondents have used at least

one form of unconventional therapy including herbal medicine26.

As per the WHO publication in the year 1994, 90% of the world’s

population use medicinal plants for curing and 81% have no access to

synthetic drugs. Traditional remedies based on natural products could be

traced back over five millennia to written documents of the early civilizations,

for example, Ayurveda in India, Pen Ts’ ao in china, Kampo in Japan and

Unani system of medicine in Near East24.

It has been estimated that in the mid-1990 over 200 companies and

research organizations all over the world are screening plant and animal

compounds for therapeutic properties. Several important drugs used in modern

medicine have come from medicinal plant research, eg, taxol/paclitaxel,

vinblastine, vincristine, topotecan, irinotecan, etoposide, teniposide, etc. Garlic

is well known for assisting immune system to fight cancer. This claim is backed

by epidemiological evidence, which suggests that garlic helps reduce the risk of

gastrointestinal tract cancer. A research article published in the Japanese

Journal of Cancer, indicates that garlic offers protection against esophageal

and stomach cancers. Research is on to investigate garlic's potential to prevent

breast, prostate and uterine cancers. Another promising natural drug

candidate is green tea. It has also demonstrated its effect against several forms

of cancer, including skin, stomach, duodenum, colon, liver, lung, prostate and

pancreas.

However, studies on plants are very limited. Only about a third of the

million or so species of higher plants have been identified and named. Of those

identified, only a few has been scientifically investigated. Nowadays the linking

of the indigenous knowledge of medicinal plants to modern scientific research

activities provides a new approach and new lead, which makes the rate of

discovery of drugs much more effective than with random collection7.

The importance of natural products is clearly enormous. About 25% of

the drugs prescribed worldwide come from plants. Out of the 252 drugs

considered as basic and essential by the WHO, 11% are exclusively of plant

origin and a significant number are synthetic drugs obtained from natural

precursor35.

Among 20,000 to 55,000 species of plants have been used globally, of

which only 15-20% of terrestrial plants have been evaluated systematically for

its pharmaceutical potential.

Major hurdles for this very slow progress are the information about

traditional system is held individually or tribally or not documented in well

established tones and is not available anywhere in the world. Thus, globally the

detailed scientific analysis of the data has information only on 14,317 species

with ethno medical data, representing 3,703 genera and 272 plant families.

This represents about 5.2% of all estimated higher plant species. Out of 8,387

(58.6%) of the ethnomedically used plants, no compound has been isolated and

no biological work was conducted38. Thus, even with this very incomplete

database global ethno medical information, there is abundant opportunity for

the discovery of new medicinal agents.

There is a wide spread belief that the natural products are less toxic when

compared to pure chemicals. Though this belief has been contested by a

number of scientists, one cannot altogether rule out the belief. It is possible

that some constituents nullify the toxic effects of other components of a plant

and the whole plant extract becomes less toxic and more useful. The drugs of

plant origin can be easily prepared and hence are cheaper than the synthetic

drugs.

Another factor, which should not be lost sight-off, is the lead to drug

design that one gets from the natural products towards the synthesis of more

active ones. The isolated pure chemical from a plant is first studied extensively

for its pure chemical structure and biological activity. Suppose the isolated

component shows some useful activity, then one can design the synthesis of a

series of analogous compounds, each differing from the other a little bit in its

structure. By careful molecular manipulation, it is possible to bring out new

drugs of real therapeutic merit39.

Research on natural products as sources of novel human therapeutics

reached peak during 1970-1980 in the Western pharmaceutical industry. More

than half drugs in the market are natural products or derived from natural

products. But, despite the record of accomplishment, working with natural

products has experienced a slow turn down during the past decade40. The

decreased prominence in pharmaceutical industry on the drug discovery from

natural products throughout the past decade can be attributed to a number of

factors:

Researchers began to look for more profitable approaches for drug

discovery using techniques such as chemistry libraries, combinational

libraries, high throughput and ultra high throughput screening. The progress

in cellular biology, molecular biology, and genomics, has increased the number

of molecular targets and provoked shorter drug discovery.

One of the precise obstacle with natural products is discovery of their

chemical structure which is important for chemical synthesis and

derivatization during optimization process. Declining interest in drugs for

infectious diseases, the vast majority of which are derived from nature, further

eroded the status of natural products

Difficulties in converting natural products into commercially viable

patented drug preparations have brought considerable neglect to the promotion

of natural products by the privately funded drug research.

This lag phase for natural medicine is now rapidly changing for a

number of reasons such as drug resistant microorganisms, adverse drug

effects of allopathic drugs and emerging new diseases where no medicines are

existing41. Moreover, pharmaceutical industry is under pressure today due to

decreased new products. The Pharma industry is taking a second look at

compounds derived from traditional sources like plants, soil, and less

traditional sources such as marine organisms. Now companies are looking for

new ways to improve their research and development department and their

productivity. After 20 years of sustained effort, the pros and cons in this area

have been more accurately realized2.

1.10. Advantages of medicines derived from plants:

The plant-derived medicines have three distinct advantages over the

more conventional techniques of phytochemical research.

The first advantage is the plant derived extracts can be directly evaluated

for biological activity rather than subjected to initial chemical isolation.

The second advantage of plant - derived medicines is that, some plant

extracts have active molecules that are very poorly soluble when found

after isolation. Plants contain many components that act as natural

soaps and increase the solubility of their chemical constituents.

The third advantage is that some medicinal plants contain more than one

active component that acts, as synergist between different elements can

be the important part of their overall therapeutic effect (www

Phytopharm. Co.uk/ prod_botanicals).

India is represented by prosperous natural biodiversity and offers a

unique opportunity for drug discovery researchers. The country is blessed with

Eastern Himalaya and Western Ghats, that are world’s 18 hotspots of plant

biodiversity and is 7th among the 16 Mega assorted countries, where 70% of the

species occur collectively. Over 7500 plant species have been reported to be

used in the Indian traditional systems including ethno medicines2.

The traditional knowledge about the plants can be obtained only by

specialists within an indigenous community - for example the shamans, bee

keepers, medicine man and master fisherman. The ethnobotanist,

pharmacognosist, plant drug researchers have to establish credibility in the

community and a relationship with the specialists based on trust. This brings

up some ethical issues on ownership to the plant information7.