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Chapter-1 INTRODUCTION Bhavik Ph. D Dissertation 1 1. INTRODUCTION 1.1 Herbal Medicine Plant kingdom had played vital role in man‟s existence on this earth. Nature has always been stands as a golden mark to amplify the outstanding phenomenon of symbiosis. Medicinal plants existing even before human being made their appearance on the earth. 1 Natural products have been derived from higher plants, microbes or animals and those can be of either terrestrial or marine or aquatic origin. Practically every country develops its own medical system, which includes the ancient civilization of China, Egypt and India. Thus, the Indian Medical system Ayurveda came into existence. The raw materials for Ayurvedic medicines were mostly obtained from plant sources in the form of crude drugs such as dried herbal powders or their extracts or mixture of products. Also, Siddha and Unani are traditional health care systems have been flourishing for many centuriesin the country. Apart from these systems there has been a rich heritage of ethanobotanical tradition of herbs by a diversity of tribal communities in the country. The medicinal preparations based on these raw materials were in the form of crude drug. Many of these reputed medicinal plants came under chemical investigation leading to the isolations of active principles with the advent of scientific methods. There was continuous activity in this area since 1800 AD and many of the well known medicinal plants were chemically analyzed and their active principles were characterized. Soon after their isolation and characterization of these compounds, either in pure state or in the form of extracts, became part of pharmacopoeias of several countries. This is where herbal medicine and modern medicine have a common link. 2,3,4 1.1.1Herbal wealth of India Now-a-days natural products are becoming an integral part of human health care system, because of popular concern over toxicity and resistance of modern drugs. India is one of 12 leading bio-diversity centers with presence of over 45,000 different plant species, 15000-18000 flowering plants, 23,000 fungi, 16,000 lichens, 18,000 bryophytes and 13 million marine organisms. From this flora 15,000 to 20,000 have good medicinal value. Among those only about 7,000 plants are used in Ayurveda, 600 in Siddha, 700 in Unaniand 30 in modern medicines.

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Chapter-1 INTRODUCTION

Bhavik Ph. D Dissertation 1

1. INTRODUCTION

1.1 Herbal Medicine

Plant kingdom had played vital role in man‟s existence on this earth. Nature has

always been stands as a golden mark to amplify the outstanding phenomenon of

symbiosis. Medicinal plants existing even before human being made their appearance

on the earth.1Natural products have been derived from higher plants, microbes or

animals and those can be of either terrestrial or marine or aquatic origin.

Practically every country develops its own medical system, which includes the ancient

civilization of China, Egypt and India. Thus, the Indian Medical system Ayurveda

came into existence. The raw materials for Ayurvedic medicines were mostly

obtained from plant sources in the form of crude drugs such as dried herbal powders

or their extracts or mixture of products. Also, Siddha and Unani are traditional health

care systems have been flourishing for many centuriesin the country. Apart from these

systems there has been a rich heritage of ethanobotanical tradition of herbs by a

diversity of tribal communities in the country.

The medicinal preparations based on these raw materials were in the form of crude

drug. Many of these reputed medicinal plants came under chemical investigation

leading to the isolations of active principles with the advent of scientific methods.

There was continuous activity in this area since 1800 AD and many of the well known

medicinal plants were chemically analyzed and their active principles were

characterized. Soon after their isolation and characterization of these compounds,

either in pure state or in the form of extracts, became part of pharmacopoeias of

several countries. This is where herbal medicine and modern medicine have a

common link.2,3,4

1.1.1Herbal wealth of India

Now-a-days natural products are becoming an integral part of human health care

system, because of popular concern over toxicity and resistance of modern drugs.

India is one of 12 leading bio-diversity centers with presence of over 45,000 different

plant species, 15000-18000 flowering plants, 23,000 fungi, 16,000 lichens, 18,000

bryophytes and 13 million marine organisms. From this flora 15,000 to 20,000 have

good medicinal value. Among those only about 7,000 plants are used in Ayurveda,

600 in Siddha, 700 in Unaniand 30 in modern medicines.

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Chapter-1 INTRODUCTION

Bhavik Ph. D Dissertation 2

The WHO estimated that 80% of the population of developing countries relies on

traditional medicines, mostly plant drugs, for their primary health care needs. Also,

modern Pharmacopoeias still contain at least 25% drugs derived from plants and

many others which are synthetic analogues built on prototype compounds isolated

from plants. Demand for medicinal plant is increasing in both developing and

developed countries due to increasing recognition of natural products, being non-

narcotic, having less side-effect, easily available at affordable prices and sometime

the only source of health care available to the poor. Medicinal plant sector has

traditionally occupied an important position in the socio-cultural, spiritual and

medicinal arena of rural and tribal lives of India.5

Demand for medicinal plant is increasing in both developing and developed countries,

and the bulk of the material trade is still from wild harvested sources on forest land

and only a very small number of species are cultivated. The expanding trade in

medicinal plants has serious implications on the survival of several plant species, with

many under serious threats to become extinct. A holistic management action plan is

necessary to formulate for assessment and management of resource base; best

harvesting and processing practices; trade issues and aspects dealing with the

intellectual property rights on the traditional medicines by the tribal people.6

1.1.2 Steps necessary for promoting herbal drugs

Phytochemistry or natural product chemistry research is the backbone of herbal

industry. For promoting use of herbals in modern medicine, phytochemistry should be

envisaged for; isolation, purification and characterization of new phytoconstituents,

use of newly isolated phytoconstituents as “lead” compound for the synthetic design

of analogues with either improved therapeutic activity or reduced toxicity and

conservation of lead phytoconstituents into medicinally important drugs.7

1.1.3 Ethno-pharmacological approach to herbal drugs

The term ethno-pharmacology refers the interdisciplinary scientific observation,

description, and experimental investigation of indigenous drugs and biological

activities. Recent interest in the use of ethno-pharmacological information of plant

drugs has greatly increased for several reasons. Scientists showed that 119 important

plant derived drugs used in one or more countries, 88 were regarded as having been

discovered as a result of being derived from a plant used in traditional medicine.8

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Bhavik Ph. D Dissertation 3

1.1.4 Practical aspects of herbal drug discovery

The stages involved in the development of pure drug from a plant source are

summarized as follow.

Collection and identification of the plant and deposition of voucher sample in

local and major herbaria.

Literature survey on the plant species selected for studies.

Preparation of extracts by using non-polar and polar solvent for initial

biological testing.

Evaluation of plant extract against a panel of biological test methods, as

exemplified by receptor biding, enzyme inhibition, and /or cytotoxicity assays.

Activity guided fractionation of the extract, by monitoring chromatographic

fraction with bioassay chosen from the panel available to the investigation.

Structure elucidation of pure active isolate using spectroscopic techniques and

chemical methods, if necessary.

Test each active compound (whether of novel or known chemical structure) in

all in vitro and in vivo biological test methods available, in order to determine

potency and selectivity of the drug.

Perform molecular modeling studies and prepare derivatives of the active

compound of interest.

Carry out large scale re-isolation of active compounds for toxicological,

pharmacological and mutation studies, when total synthesis is not practical.

Clinical trials (phase I – III).

1.1.5 Current status of herbal drugs

Recent years newer and newer diseases are posing threat to humanity. In fact diseases

are not new but are detected newly. Despite this, WHO had taken the vouch of

providing „Health for all‟ by 2000 AD. In spite of stupendous advances made by

modern medicine, the present century has many more health problems than earlier

centuries. Drugs for viral diseases like AIDS, certain type of cancers, arthritis,

Parkinsonism are yet to come. The newer concepts about herbal drugs have

immunomodulators and are recognized for prophylactic and preventive therapy.

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Bhavik Ph. D Dissertation 4

Surprisingly, a recent survey revealed that more than 50% of all prescription drugs

issued by rational physicians are either directly derived from the natural sources or

synthesized from the natural models as the sole ingredient or as one of the several

ingredients. It seems certain that the continued scientific study of medicinal plants

afford a plethora of novel, structurally diverse and bioactive compounds.

Multidisciplinary research on plants has lead to many new drugs, as well as prototype

active molecules and biological tools.9

1.1.6 Future prospects in herbal medicines

At the moment, scientific research on medicinal plants is continuing most intensely in

research institutes, universities and pharmaceutical laboratories as well as in the

clinics of many developed countries. This research is oriented mainly in two

directions. Firstly the active ingredients of plants that have long been known for their

healing properties are been investigated. The second sphere of basic research has led

to the discovery of new kinds of medicinal plants and new drugs from the more

remote regions of the world where new species with unknown substances still remain

to be looked into.

Each and every traditional medicine are tested and validated scientifically. CSIR,

New Delhi, already involved in this filed, validated about 350 formulations for

different activities. The WHO has emphasized the need to ensure the quality control

of herbs and herbal formulations by using modern techniques. Several countries have

herbal pharmacopoeias and lay down monographs to maintain their quality. The

Ayurvedic pharmacopoeia of India which was recommends basic quality parameters

for eighty common Ayurvedic herbal drugs.10

1.2Standardization

Standardization is an essential factor for polyherbal formulation in order to assess the

quality of the drugs based on the concentration of their active principle. It is very

important to establish a system of standardization for every plant medicine in the

market, since the scope for variation in different batches of medicine is enormous.

Plant material when used in bulk quantity may vary in its chemical content and

therefore, in its therapeutic effect according to different batches of collection e.g.

collection in different seasons and/or from sites with different environmental

surroundings or geographical location. WHO has appreciated the importance of

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Bhavik Ph. D Dissertation 5

medicinal plants for public health care in developing nations and has evolved

guidelines to support the member states in their efforts to formulate national policies

on traditional medicine and to study their potential usefulness including evaluation of

its quality, safety and efficacy.11

The process of evaluating the quality and purity of crude drugs by means of various

parameters like morphological, microscopically, physical, chemical and biological

observation is called standardization.12

Standardization involves adjusting the herbal drug preparation to a defined content of

a constituent or a group of substances with known therapeutic activity by adding

excipients or by mixing herbal drugs or herbal drug preparations. Botanical extracts

made directly from crude plant material show substantial variation in composition,

quality, and therapeutic effects. The presence of the word “Standardized” on a

supplement label does not necessarily indicate product quality. When the active

principles are unknown, marker substances should be established for analytical

purposes and standardization.

Fig 1.1: Parameters for standardization and quality evaluation of herbal drugs

1.2.1 WHO guidelines for standardization of herbal formulations.13,14

The standardization of crude drug materials includes the following steps

i. Authentication: Herbal drugs should be authenticated by considering

parameters like; stage of collection, parts of the plant collected, regional

status, botanical identity like phytomorphology, microscopy and

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Bhavik Ph. D Dissertation 6

histological analysis, taxonomical identity, etc.

ii. Foreign matter: Herbs collected should be free from insect parts or

animal excreta and other contaminants like dust, soil, stones and

extraneous matter etc. Foreign matters also include parts or the organ of

the plant other than require for drug by definition or beyond limits set by

the WHO guidelines.

iii. Organoleptic evaluation: Sensory characters, taste, appearance, odour,

texture etc of the drug, are the various Organoleptic parameters should be

evaluated for identification and purity before undertaking further tests.

iv. Presence of important diagnostic tissues: Microscopically identity of

medicinal plant material is indispensable for the identification of broken

or powdered material. An examination by microscopy alone cannot

always provide complete identification, though when used in association

with other analytical method.

v. Ash values: The amount of material remaining after ignitionis called total

ash. It is also further determined by acid insoluble ash and water soluble

ash.

vi. Extractive values: This determines the amount of active constituents

extracted with different solvents like water, alcohol, ether, chloroform etc.

from a given amount of medicinal plant material.

vii. Moisture content and volatile matter: Determination of moisture

content or loss on drying helps in the estimation of the amount of volatile

matter. It is more appropriate for substances contain water as the only

volatile constituent. An excess of water in medicinal plant material will

encourage microbial growth so that limits for water content should be set

for every plants.

viii. Chromatographic and spectroscopic evaluation: TLC, HPTLC, HPLC

methods will provide qualitative and semi quantitative information about

the main active constituents present in the crude drug as chemical markers

in the TLC fingerprint evaluation of herbals. The quality of the drug can

also be assessed on the basis of the chromatographic fingerprint.

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Bhavik Ph. D Dissertation 7

ix. Heavy metals: Medicinal plant materials with heavy metals like; arsenic,

lead, mercury and cadmium can be contaminated due to many causes

including environmental pollution and traces of pesticides.

x. Pesticide residue: WHO and Food and Agricultural Organization (FAO)

have set limits of pesticides, which are usually present in the herbs. These

pesticides are mixed with the herbs during the time of cultivation. Mainly

pesticides like DDT, BHC, toxaphene, and aldrin cause serious side-

effects in human beings if the crude drugs are mixed with these agents.

xi. Microbial contamination and afflatoxins: Usually medicinal plants

containing bacteria and molds are coming from soil and atmosphere.

Analysis of the limits of E. coli and molds clearly throws light towards the

harvesting and production practices. The substance known as afflatoxins

will produce serious side-effects if consumed along with the crude drugs.

Afflatoxins should be completely removed or should not be present.

xii. Radioactive contamination: Microbial growth in herbals is usually

avoided by irradiation. This process may sterilize the plant material but

the radioactivity hazard should be taken into account. The radioactivity of

the plant samples should be checked accordingly to the guidelines of

International Atomic Energy (IAE) in Vienna and that of the WHO.

In order to obtain quality oriented herbal products care should be taken right from the

proper identification of plants; season and area of collection, extraction, isolation and

verification process.

1.2.2 Quality control parameters for herbal formulations

i. Physical parameters: It include colour, appearance, odour, clarity,

viscosity, moisture content, ash values, pH, disintegration time, friability,

hardness, flow property, flocculation, sedimentation and settling rate.

ii. Chemical parameters: It includes limit tests for heavy metal, extractive

values, chemical assays for active constituents, etc.

iii. Chromatographic analysis of herbals: Chromatographic analysis can be

carried out using TLC, HPLC, HPTLC and GC, UV, Fluorimetry, GC-

MS, etc.

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iv. Microbiological parameters: It includes total viable content, total mold

count, total entero-bacteriaceae and their count.

1.3Antioxidants15,16,17,18,19

Hyper physiological burden of free radical causes imbalance in homeostatic

phenomenon between oxidants and antioxidants in the body. The imbalance leads to

oxidative stress that is being suggested as the root cause of aging and various human

diseases like arteriosclerosis, stroke, diabetes, cancer and neurodegenerative diseases

such as Alzheimer‟s and Parkinsonism. Therefore research in recent past have

accumulated enormous evidence advocating enrichment of body system with

antioxidants to correct vitiated homeostasis and prevent onset as well as treat the

disease caused due to free radical and related oxidative stress. Stress, smoking, drugs

and dietgenerates excessive free radicals in human body.

Antioxidants have defined as the substance those in small quantities, able to prevent

or greatly retard oxidation of easily oxidisable material such as fats. Antioxidants may

exert their effect by different mechanisms such assuppressing the formation of active

species by reducing hyperoxides (ROO)and H2O2 and also by sequestering metal ions

scavenging active free radicals, repair and/or clearing damage. Mechanisms of radical

scavenging activity of antioxidants are well available

1.3.1 Characteristics

a) The presence of phenolic pharmacophore in antioxidant molecules.

b) An antioxidant should have electron-donating substituents.

c) Substitution on ortho positions are important in determining the stability of

phenoxy radical.

d) Presence of nucleophilic electron donating properties of polyphenols present in

the flavanol (tea) may be one of the important mechanisms of action involved in

inhibition of carcinogenesis.

Antioxidant plays an important role in removing such free radicals. Free radicals

reaction is an important pathway in a wide range of unrelated biological systems.

Amongst the many ways to chemically injure and kill cells, an important class of

reaction is that producing free radicals intermediates which trigger a network of

multifarious disturbances because of ubiquity of molecular oxygen in aerobic

organism and its ability to accept electron. Oxygen derived free radicals are often

mediators or products of normal pathological or toxic free radical reaction. A vast

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Bhavik Ph. D Dissertation 9

number of circumstantial evidence implicates oxygen derived free radicals (especially

superoxide and hydroxyl free radical) and high-energy oxidants (such as

peroxynitrile) are as mediators of shock inflammation and ischemia reperfusion

injury. Thus, free radical scavenging is very essential for preventing organ injury

associated with shock, inflammation and ischemia reperfusion injury.

Naturally, there is a dynamic balance between the amount of free radicals generated in

the body and antioxidants to quench or scavenge them and protect the body against

their deleterious effects. However, the amount of free radicals protective antioxidant

principles present under normal physiological condition are only to cope with the

physiological role of free radical generation. Any addition burden of free radicals

eighter from environment or produced within the body, can tip the free radical (pro-

oxidant) and anti free radical (anti-oxidant) balance leading to oxidative stress, which

may result in tissue injury. These free radicals are chemical species possessing an

unpaired electron that can be considered as fragment of molecules and which are

generally extremely reactive and short lived. They are produced continuously in cells

eighter as accidental by products of metabolism or deliberately during phagocytises.

1.3.2Free radical’s formation

The haemolytic cleavage of a covalent bond of a normal molecule, with each

fragment retaining one of the paired electrons; by loss of single electron from a

normal molecule or by the addition of a single electron to a normal molecule. Electron

transfer is a far more common process in biological systems, than the other two. The

most important free radicals in biological systems are radical derivative of oxygen.

With increasing acceptance of free radicals as common and important bio-chemical

intermediates, they have been implicated in very large number of human diseases.

Thus free radical scavenging is very essential for preventing organ injury associated

with shock, inflammation and ischemia or reperfusion. Plants and its products are

known to possess excellent antioxidant properties and play a significant role in

preventing the conditions due to the excessive free radicals.

1.3.3In-vitro antioxidant assay method

Various antioxidant activity methods have been used to monitor and compare the

antioxidant activity of foods. These analytical methods measure the radical

scavenging activity of antioxidants against free radicals like DPPH, the hydroxyl

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Bhavik Ph. D Dissertation 10

radical or the Peroxyl radical (ROO), superoxide anion radicalO2. The various

methods used to measure the antioxidant activity of various extracts can give varying

results depending on the specificity of the free radical being used as reactant. The

following reactants are being used to determine the antioxidant activity.

a. Malondialdehyde (MDA)

b. Thiobarbituric acid-reactive substances(TBARS)

c. 2,2-aznobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)

d. 2,2-azobis(2-amidinopropane)(AAPH)

Many studies have been performed to identify anti-oxidant compounds with

pharmacological activity and a limited toxicity. The phytochemical analysis of plants

used traditionally has revealed a large number of compounds including flavonoids,

vitamins, carotenoidsand polyphenols, which have been proved to have potent anti-

oxidant properties. The herbal mixture preparations of Indian traditional medicines

have also anti-oxidant activity arising from their content of plants with antioxidant

principles that act probably in a synergistic way. This hypothesis along with the lack

of toxicity can be important to understand their use in past as well as now a day.

Based on the concept, present study was undertaken to evaluate the antioxidant

potentials of Bhunimbadi churna, which has been explored for their antioxidant

potential through various in vitro models.

A general recommendation to the consumer is to increase the intake of foods rich in

anti-oxidant compounds having well-known healthy effects. As a consequence, these

evidences accelerated the search for antioxidants principles, which led to the

identification of natural re-sources and isolation of active antioxidant molecules.

Plants with potential antioxidant activities are given in Table 1.1

Table 1.1: Medicinal plants with antioxidant properties20,21,22

Sr No. Botanical name Family Part used

1 Achilleamillefolium Asteraceae Whole plant

2 Acoruscalamus Araceae Rhizome

3 Archangelicaofficinalis Umbelliferae Leaf

4 Artemisia vulgaris Compositae Whole plant

5 Carumcarvi Umbelliferae Fruit

6 Chelidoniummajus Papaveraceae Whole plant

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Bhavik Ph. D Dissertation 11

7 Curcuma longa Zingiberaceae Rhizome

8 Cynamonumzeylanicum Lauraceae Seed

9 Cyperusrotundus Cyperaceae Root, Stem

10 Echinacea purpurea Asteraceae Leaf

11 Epilobiumhirsutum Onagraceae Whole plant

12 Glycyrrhiza glabra Fabaceae Stem

13 Herniaraglebra Caryophyllaceae Whole plant

14 Holarrhenaantidysenterica Apocynaceae Seed, stbk

15 Humuluslupulus Cannabaceae Cone

16 Hypericumperforatum Hypericaceae Whole plant

17 Inulahelenium Compositae Root

18 Juglansregia Juglandaceae Leaf

19 Levisticumofficinale Umbelliferae Whole plant

20 Marrubiumvulgare Labiatae Whole plant

21 Melisa officinalis Labiatae Whole plant

22 Myristicafragrans Myristicaceae Fruit

23 Origanumvulgare Labiatae Whole plant

24 Petroselinumsativum Umbelliferae Root

25 Picrorrhizakurroa Scrophulariaceae. Rhizome

26 Piper longum Piperaceae Fruit

27 Piper nigrum Piperaceae Fruit

28 Plumbagozeylanica Plumbaginaceae Root

29 Polygonumaviculare Polygonaceae Whole plant

30 Salvia officinalis Labiatae Whole plant

31 Silybummarianum Compositae Seed

32 Swertiachirata Gentianaceae Whole plant

33 Syzygiumaromaticum Myrtaceae Fruit

34 Thymus vulgaris Lamiaceae Leaf

35 Valerianaofficinalis Valerianaceae Root

36 Zingiberofficinale Zingiberaceae Rhizome

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Bhavik Ph. D Dissertation 12

1.4 Diabetes

There are many diseases that are caused due to genetically disorders, and one of this is

Diabetes Mellitus. Diabetes is a disorder of metabolism (the way our bodies use

digested food for growth and energy). Most of the food we eat is broken-down by the

digestive juices into a simple sugar called glucose. Glucose is the main source of fuel

for the body. After digestion, the glucose passes into bloodstream where it is available

for body cells to use for growth and energy. Glucose gets into the cells in presence of

insulin, a hormone produced by the pancreas.

Normally, pancreas is automatically producing the right amount of insulin to move

the glucose from our blood into our cells. If body doesn‟t make enough insulin or the

insulin doesn't work right, the sugar cannot get into the cells. It stays in the blood.

This makes high levels of glucose (or sugar) in the blood producing hyperglycemia.

As a result, glucose builds up in the blood, overflows into the urine, and passes out of

the body in urine (glucosuria). Thus, the body loses its main source of fuel even

though the blood contains large amounts of glucose. Thus Diabetes is a chronic

condition that occurs when the pancreas does not produce enough insulin or when the

body cannot effectively use the insulin.23,24

There are more than 125 million people with diabetes in the world today and this

number is expected to approach 220 million. It is also estimated that there are 30 to 33

million diabetics in India now, and every fourth diabetics in the world today is an

Indian. Indians are genetically more susceptible to diabetes and the WHO predicts the

number of diabetes in India would group to 80 million by 203025

.There are two types

of Diabetes; Diabetes insipidus and Diabetes mellitus.

1.4.1 Diabetes Insipidus: Despite the similar names diabetes insipidus is not related

to diabetes mellitus. Some people with diabetes insipidus have kidneys that don‟t

concentrate urine very well (meaning their urine is more diluted). They might wake

up 2 or 3 times in the night to urinate. People with diabetes insipidus are thirsty all the

time. They often want to drink liquids every hour.

Etiology of Diabetes insipidus suggests that in some people, a part of the brain

doesn‟t make enough anti diuretic hormone (ADH).In other people, the kidneys do

not work with this hormone the way they should. Most people with diabetes insipidus

get it after an injury to the head or after brain surgery or in case of a brain tumor.26

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Bhavik Ph. D Dissertation 13

1.4.2 Diabetes mellitus: It is a clinical syndrome characterized by hyperglycemia due

to the pancreas may produce little insulin, if any. In other cases, the pancreas may

produce some insulin, but the cells do not respond to it. Diabetes mellitus is

characterized by hyperglycemia, glucosuria, negative nitrogen balance and sometimes

ketonemia.27

It is classified as follows

Type I: Immune mediated - Juvenile onset /Insulin dependent (could be in

children with a more rapid onset or adults with a slower onset „late

autoimmune diabetes of adults‟),

Type II: Insulin resistant -Adult onset diabetes/non-insulin dependent diabetes

A. Gestational diabetes mellitus

B. Other specific types (e.g. certain genetic defects; drug induced; etc)28

Type I: It is characterized by severe lack of insulin due to the destruction of most or

all of the beta cells in the islets of Langerhans by an autoimmune process, usually

leading to absolute insulin deficiency. The onset is usually acute, developing over a

period of a few days to weeks. Over 95% of persons with type 1 diabetes mellitus

develop the disease before the age of 25 and most often between the ages of 10 and

16, with an equal incidence in both sexes and an increased prevalence in the white

population. Type I diabetes is invariably treated with insulin.

Type II: Insulin resistance in peripheral tissue and an insulin secretary defect of the

beta cell of pancreas, so that less glucose is produced, and to an impairment of

insulin's ability to stimulate the uptake of glucose in muscles and other tissues. The

cause of this insulin resistance has not yet been fully established, but may involve

defects in the action of insulin after it has bound to the insulin receptor on the surface

of cells. This is the most common form of diabetes mellitus and is highly associated

with a family history of diabetes, older age, obesity and lack of exercise.29,30

A. Gestational diabetes: Occur during pregnancy, sensitivity to insulin

decreases (placental hormones affect glucose tolerance). Beta cells may not be

able to meet this increased need for insulin gestational diabetes. They are

occurs in up to 14% of pregnancy. This increases subsequent risk of

developing type II diabetes. Increased risk for perinatal mortality and neonatal

morbidity.

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Bhavik Ph. D Dissertation 14

B. Other types of diabetes mellitus: Specific genetic/molecular defects have

been identified in a minority of what were considered type II diabetes:

1) Genetic defects of function of beta cell. e.g. Hepatic nuclear factor 4

alpha - autosomal dominant condition of impaired insulin secretion;

early onset and slowly progressive; type I(mature onset diabetes of the

young).e.g. Mutation of mitochondrial DNA

2) Genetic defects in the action of insulin: e.g. insulin receptor - (severe

insulin resistance) Lipoatrophic diabetes

3) Endocrine disorders

Diseases of the pancreas, e.g. pancreatitis, neoplasia, cystic

fibrosis, haemochromatosis

Endocrinopathies, e.g. acromegaly, Cushing's syndrome,

hyperthyroidism, pheochromocytoma

4) Drug/chemical induced, e.g. vacor, pentamidine, glucocorticoids,

thiazides, dilantin

5) Infection, e.g. congenital rubella, cytomegalo virus

6) Immune mediated (uncommon), e.g. Stiff man syndrome, anti-insulin

receptor antibodies.

1.4.3 Causes of Diabetes

a. Heredity i.e. family history of late onset diabetes

b. Obesity i.e. over weight

c. Lack of physical activity i.e. sedentary life style

d. Women with prior gestational diabetes

e. Stress and Strain31

1.4.4 Diabetes Symptom

A. Symptoms of type I diabetes may include

Increased thirst and urination

Blurred vision

Feeling very hungry

Weight loss in spite of increased eating

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B. Symptoms of type II diabetes may include

Feeling tired or ill

Frequent urination (especially at night)

Unusual thirst

Weight loss

Blurred vision

Frequent infections

Slow healing of sores.

Having dry, itchy skin

Having tingling in the feet.

1.4.5 Complications occur in diabetes

Acute Complications

Type – I Diabetes (IDDM)

Due to illness or fever, insulin requirement increases if additional requirement

of insulin is not met with, a diabetic coma can develop.

Diabetic Ketoacidosis – Appearance of large amount of glucose along with

„Ketone‟ bodies in urine.

Type – II Diabetes (NIDDM)

Dehydration coma – Loss of excessive amounts of water and salt.

Skin problems.

Long term complications

Eyes: Progressive loss of vision, leading to blindness, diabetes is among the

three common causes of blindness today.

Heart: Diabetics are very prone to developing high blood pressure.

Blood vessels and circulation: The arteries may develop fat deposits

hindering flow of blood, affecting the blood supply to extreme parts of limbs.

An injury of such limbs may develop gangrene, which may lead to an

amputation.

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Kidneys: More susceptible to infections of the urinary bladder and Kidneys. It

may also lead to failure of kidney functions.

Nervous System: Diabetes affects the nerves leading to loss of sensation. In

contrast certain diabetics may suffer from tingling or burning sensation in

extreme parts of limbs.32

1.4.6 Prevention of diabetes mellitus

It may not be possible to prevent diabetes in all cases but even delay in its onset is an

achievement. First step is the identification of high-risk groups. These high-risk

individuals follow.

Regular exercise to maintain normal body weight

Obese persons should undergo diet control and exercise to reduce weight.

Avoid fast food and take original Indian lacto vegetarian food

Avoid stressful life.

Meditation and yoga can also help.

Two diabetics should not marry.

If above non-pharmacological methods fail drugs may be used for prevention of

diabetes.33

1.4.7 Drug used in diabetes

Oral Hypoglycemic agents

1) Sulphonylureas : Gibenclamide, Tolbutamide,

Chlorpropamide, Tolazamide,

Glipizide, Gliclazide

2) Bigaunides : Metformin,Phenformin

3) α-Glucosidase inhibitors : Acarbose, Miglitol, Voglibose

4)Thiozolindinedione derivatives : Troglitazone, Ciglitazone

5) Inhibitors or gluconeogenesis : Dichloroacetic acid (DCA)

6) Inhibitors of lypolysis : Acipimox (Nicotinic acid analogue)

7) Fatty acid oxidation : Tetrahydecylglycidicacid (TDGA)

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Oral anti-diabetic agents, act only on a part of the pathogenic process, may not

produce any cure and prevent all the complications of diabetes. Insulin cannot be used

orally and continuous insulin injection has many side effects and toxicity. Thus,

people have started looking at the ancient healing systems. Since ancient times many

medicinal plants claim to control the diabetes in humans but systematic evaluation of

them are not done yet. The lack of documentation and stringent quality control are the

key obstacles, have hindered the acceptance of the alternative medicines in the

developed countries. In recent times, many studies have been carried out in the search

of a proper plant drug that would be effective in diabetes mellitus. Medicinal plants

with proven antidiabetic and related beneficial effects used in treatment of diabetes

are compiled in table 1.2.

Table 1.2: Medicinal plants with antidiabetic properties34,35,36

Sr No. Botanical name Family Part used

1 Acacia Arabica Mimosaceae Bark

2 Acacia malanoxylon Fabaceae Root

3 Acacia modesta Fabaceae Seed

4 Adhatodavasica Acanthaceae Leaves

5 Aeglemarmelos Rutaceae Leaves & Root

6 AlangiumSalvifolium Alangiaceae Leaves

7 Allium cepa Liliaceae Bulb

8 Alliumsativum Liliaceae Bulb

9 Aloe barbadensis Liliaceae Leaves

10 Anacardiumoccidentale Anacradiaceae Leaves & bark

11 Areca catechu Arecaceae Seed

12 Artemisia pallens Compositae Arial parts

13 Avena sativa Cyperaceae Seed

14 Azadirachtaindica Meliaceae Leaves

15 Boerhaviadiffusa Nyctaginaceae Leaves

16 Bougainvillea pectabilis Nyctaginaceae Leaves

17 Brassica oleracea Brassicaceae Leaves

18 Cassia fistula Leguminoseae Seeds

19 Cassia occidentalis Febaceae Seed & Bark

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20 Cocciniaindica Cucurbitaceae Root

21 Cyperusrotundus Cyperaceae. Rhizome

22 Emblicaofficinalis Myrtaceae Seed

23 Eucalyptus citriodora Myrtaceae Leaves

24 Eugenia jambolana Myrtaceae Seed

25 Ficusreligiosa Moraceae Bark & Root

26 Gmelina arborea Verbenaceae Fruit

27 Gymnemasylvestre Asclepiadaceae Leaves

28 Holarrhenaantidysenterica Apocynaceae Seed

29 Holarrhenaantidysenterica Apocynaceae Stem Bark

30 Holostemaannualare Asclepiadaceae Root

31 Hordeumvulgare Gramineae Root

32 Ipomoea nil Convolvulaceae Whole plant

33 Mangiferaindica Anacardiaceae Leaves

34 Momordicacharantia Cucurbitaceae Fruits

35 Morus alba Moraceae Leaves

36 Picrorhizakurroa Scrophulariaceae Rhizome

37 Piper nigrum Piperaceae Fruit

38 Piper longum Piperaceae Fruit

39 Pinusroxburghii Pinaceae Bark & Root

40 Plumbagozeylanica Plumbaginaceae Root

41 Pterocarpusmarsupium Leguminoseae Bark &Wood

42 Saussurealappa Compositae Root

43 Swertiachirata Gentianaceae Whole plant

44 Smilax lanceifolia Smilacaceae Root

45 Trigonellafoenum-graecum Leguminoseae Seed

46 Thevetiaperuviana Apocynaceae Bark

47 Zanthoxylumacanthopodium Rutaceae Leaf

48 Zingiberofficinale Zingiberaceae Rhizome

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Marker compound, chemical constituents within a medicinal that can be used to verify

its potency, isolated for direct use as drugs and lead compounds or pharmacological

agents.Here given some active agents isolation from medicinal plants used as an

antidiabetic agent are given in table 1.3.

Table 1.3: Active antidiabetic principles isolated from the medicinal plants37,38

Sr. No Botanical name Part used Active Principles (Marker)

1 Acontiumcarmichaeii Root Aconitan A,B,C &D

2 Anemarans Rhizomes Anemarans A, B, C&D

3 Atractylodes japonica Rhizome Glycons A,B,C,D Atractants

4 Bauhinia pururea Aerial part Quercetin

5 Capsicum annum Fruit Capsaicin

6 Clytiarichardiana Leaves SaudinRhamnoside

7 Cyperusrotundus Rhizome Cyperene

8 Dioscorea japonica Rhizome Glycans A,B,C,D,E,F

9 Galegaofficinalis Seed Galegin

10 Holarrhenaantidysenterica Seed Conessine

11 Holarrhenaantidysenterica Stem Bark Conessine

12 Lathyrus japonica Seed Lathyrines

13 Lepidiumruderale Aerial part Lepidine

14 Picrorhizakurroa Rhizome Picroside I, II

15 Piper nigrum Fruit Piperin

16 Piper longum Fruit Piperin

17 Potatorumancisteroides Aerial part Tormetic acid

18 Plumbagozeylanica Root Plumbagin

19 Swertiachirata Whole plant Sawertiamarine, Mangeferin

20 Zingiberofficinale Rhizome 6,8,10-gingerol

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