DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

“Development and management of nutraceuticals”

Project submitted in the partial fulfilment of the degree

Of
Bachelor of Pharmacy
In the faculty of Pharmaceuticals Science,
Bharti Vidyapeeth (Deemed to be university), Pune.

By

SONALI SURESH MORE

B. Pharm (Sem. VIII)
Guided by
Dr. MUGDHA SURYAWANSHI
(Assistant professor, Department of chemistry)

Poona College of pharmacy, Pune

BHARTI VIDYAPEETH (DEEMED TO BE) UNIVERSITY, PUNE.

POONA COLLEGE OF PHARMACY ERANDWANE,
PUNE- 411038, INDIA

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

CERTIFICATE

This is to certify that the work presented in the dissertation entitled

“Development and Management of Nutraceuticals” for the degree of
Bachelor of Pharmacy in the Faculty of Pharmaceutical Sciences has been
carried out by Sonali Suresh More in Bharati Vidyapeeth (Deemed to be)
University, Poona College of Pharmacy, Pune under the guidance of Dr.
Mugdha Suryawanshi (Assistant Professor, Department of Chemistry)
Bharati Vidyapeeth (Deemed to be) University, Poona College of Pharmacy,
Pune.

Date:
Dr. A. P. Pawar
Place: In-charge Principal
Poona College of Pharmacy,
Pune - 411038

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

CERTIFICATE

This is to certify that the work presented in the dissertation entitled

“Development and Management of Nutraceuticals” for the degree of
Bachelor of Pharmacy in the Faculty of Pharmaceutical Sciences has been
carried out by Sonali Suresh More in Bharati Vidyapeeth (Deemed to be)
University, Poona College of Pharmacy, Pune under the guidance of Dr.
Mugdha Suryawanshi Assistant Professor, Department of Chemistry, Bharati
Vidyapeeth (Deemed to be) University, Poona College of Pharmacy, Pune.

Date: Dr. Mugdha Suryawanshi

Place: (Assistant professor, Department of chemistry)
Poona college of pharmacy
Pune: 411038

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ACKNOWLEDGEMENT

I would like to express my special thanks of gratitude to my guide Dr.

Mugdha Suryawanshi for her earnest, precious and enthusiastic
support which made this project completion possible. I am thankful to
her for constantly guiding me throughout my project work and
completion of my project.

My foremost reverence and gratitude to Prof. Dr. S. S. Kadam

(Honorable Chancellor) and Dr. M. M. Salunkhe (Vice Chancellor of
Bharati Vidyapeeth) for instrumental amenities made available to the
department of pharmacy. I am short of words to convey my deep sense
of gratitude to our principal Dr. A. P. Pawar & Vice Principal Dr. J. R.
Rao and Dr. Varsha Pokharkar for their precious guidance.

I would also like to convey my special thanks to all the faculty members
and non-teaching staff for their constant support throughout my project
work.
At last, I take this opportunity to thank my family and friends for their
unconditional support and guidance.

Date: Miss. Sonali Suresh More

Place: B. Pharm (Sem. VIII)
Bharti Vidyapeeth (deemed to be) University,
Poona college of pharmacy
Pune: 411038

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INDEX

Sr. No. Title Page No.

1. Introduction to nutraceutical 06-09

2. Development of nutraceuticals 10-11

3. Categories of nutraceuticals 12-17

4. Areas of concerns 18

5. Regulatory aspects 19

6. Management of nutraceuticals in osteo 20-25

arthritis

7. Nutraceutical and cancer 26-27

management

8. Etiology of cancer 28-32

9. Nutraceutical management in diabetes 33-39

Meletus

10. References 40-42

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OVERVIEW OF NUTRACEUTICALS

Nowadays, nutraceuticals have received high interests due to their

potential nutritional and safety profile, other than therapeutic capability.
Pharmaceutical and nutritional companies are aware of the changing
trends which are due to the advantages of these compounds. Most of the
nutraceuticals possess multiple therapeutic benefits.

Nutraceuticals is a broad umbrella term that is used to describe any

product derived from food sources with extra health benefits in addition
to the basic nutritional value found in foods. They can be considered
non-specific biological therapies used to promote general well-being,
control symptoms and prevent malignant processes. India has had a rich
heritage of herbal medicines and supplements which provides
physiological benefits and boosts immunity against diseases.
Transformation in food habits, less physical work, more desk jobs have
made people more vulnerable to lifestyle ailment. The average urban and
semi-urban Indian is becoming more conscious about health and
fitness. This is providing a massive growth opportunity for
nutraceutical industry in India. Categorizing nutraceuticals
Nutraceuticals can be organized in several ways. Some of the most
common ways of classifying nutraceuticals can be based on food
sources, mechanism of action, chemical nature etc.
The food sources used as nutraceuticals are all natural and can be
categorized as:
1. Dietary Fibre

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2. Probiotic
3. Prebiotic
4. Polyunsaturated fatty acids
5. Antioxidant vitamins
6. Polyphenols

Dietary Fibre
Dietary fibres mostly include non-starch polysaccharides (NSP) such as
celluloses, hemicelluloses, gums and pectin, lignin, resistant dextrin and
resistant starches. Food’s rich in soluble fibre include fruits, oats, barley and
beans. Dietary fibres may be divided into two forms: -
 Insoluble dietary fibre (IDF), which includes celluloses, some
hemicelluloses and lignin which is fermented to a limited extend
in the colon.
 Soluble Dietary Fibre (SDF), which includes β glucans,
pectin, gums, mucilage and hemicelluloses that are fermented
in the colon.

Polyunsaturated fatty acids (PUFA)

PUFAs are also called “essential fatty acids” as these are crucial to
the body’s function and are introduced externally through the diet.
PUFAs have two subdivisions: omega-3- (n-3) fatty acids and omega-
6-(n-6) fatty acids. The major omega-3-fatty acids are α-linolenic acid
(ALA), Eicosapentanoic acid (EPA), Docosahexanoic acid (DHA).
EPA and DHA are found mainly in fatty fishes such as mackerel,
salmon, herring, trout, blue fin tuna and in fish oils.

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Probiotics
A probiotic can be defined as live microbial feed supplement,
which when administered in adequate amounts beneficially
affects the host animal by improving its intestinal microbial
balance. Probiotics generally include the following categories
of bacteria: -
 Lactobacilli such as L. acidophilus, L.casei, L. delbrueckii subsp.
Bulgaricus, L. brevis, L. cellobiosus.
 Gram-positive cocci such as Lactococcus lactis, streptococcus
salivarius subsp. Thermophiles, Enterococcus faecium.
 Bifidobacteria such as B. bifidun, B.infantis, B. longum.

Prebiotics
Prebiotics are dietary ingredients that beneficially affect the host by
selectively altering the composition or metabolism of the gut
microbiota. These are short-chain polysaccharides that have unique
chemical structures that are not digested by humans; in particular
fructose-based oligosaccharides that exist naturally in food or are added
in the food.
The prebiotic consumption generally promotes the Lactobacillus and
Bifidobacterial growth in the gut, thus helping in metabolism.
Vegetables like chicory roots, banana, tomato, alliums are rich in
fructo-oligosaccharides. Some other examples of these
oligosaccharides are raffinose and stachyose, found in beans and peas.

Antioxidant vitamins
Vitamins like vitamin C, vitamin E and carotenoids are collectively
known as antioxidant vitamins.
These vitamins act both singly as well as synergistically for the
prevention of oxidative reactions leading to several degenerative
diseases including cancer, cardiovascular diseases, cataracts etc. These
vitamins are abundant in many fruits and vegetables.

Polyphenols
Polyphenols form a large group of phytochemicals, which are
produced by plants as secondary metabolites to protect them from
photosynthetic stress, reactive oxygen species.
There are approximately 8,000 different classes of polyphenols, the

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most important being flavonols, flavones, flavan-3-ols, flavanones and

anthocyanins.
These apart, polyphenols also possess antioxidant, anti-
inflammatory, anti-microbial, cardio- protective activities and play
a role in the prevention of neurodegenerative diseases and diabetes
mellitus.

Spices
Spices are esoteric food adjuncts that are used for thousands of years
to enhance the sensory quality of foods.
Dietary spices in their minute quantities have an immense
influence on the human health by their anti-oxidative,
chemopreventive, anti-mutagenic, anti-inflammatory, immune
modulatory effects on cells and a wide range of beneficial effects
on human health by the action of gastrointestinal, cardiovascular,
respiratory, metabolic, reproductive, neural and other systems.

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Development of Nutraceuticals
Consumers are deeply concerned about how their health
care is managed, administered and priced. They are
frustrated with the expensive, high- tech, disease-
treatment approach predominant in modern medicine; the
consumer is seeking complementary or alternative
beneficial products and the red tape of managed care
makes nutraceuticals particularly appealing.
Nutraceuticals (often referred to as phytochemicals or
functional foods) are natural bioactive, chemical
compounds that have health promoting, disease
preventing or medicinal properties. Nutraceuticals are
found in a mosaic of products emerging from
(a) the food industry,
(b) the herbal and dietary supplement market
(c) pharmaceutical industry
(d) the newly merged pharmaceutical/ agribusiness/ nutrition
conglomerates.
The present article reviews the general concept, categories, research
developments, areas of concern and regulatory aspects of nutraceuticals.
The term ‘nutraceutical ’was coined in 1979 by Stephen DeFelice,
founder and chairman of the Foundation for Innovation in Medicine
located in Cranford, New Jersey. It was defined as ‘a food or part of
food, that provides medical or health benefits, including the prevention
and treatment of disease Nutraceuticals may range from isolated
nutrients, herbal products, dietary supplements and diets to genetically
engineered ''designer'' foods and processed products such as cereals,
soups and beverages. Doubtlessly, many of these products possess
pertinent physiological functions and valuable biological activities with
the passage of the Dietary Supplement Health and Education Act of
1994, the definition of nutraceuticals has been expanded to include
vitamins, minerals, herbs and other botanicals, amino acids and any
dietary substance for use by humans to supplement the diet by
increasing total dietary intake and subsequently increased the use of
nutraceuticals dramatically However, functional food concept is
different from nutraceuticals and can be defined as food products to be
taken as part of the usual diet in order to have beneficial effects that go
beyond what are known as traditional nutritional effects The goal of
achieving an optimal or maximal state of nutrition and health is
becoming an increasing challenge with the introduction of many
nutraceuticals the ascribed health benefits of nutraceuticals are legion.

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Various products are claimed not only to reduce the risk of cancer and
heart disease but also to prevent or treat hypertension, high cholesterol,
excessive weight, osteoporosis, diabetes, arthritis, macular degeneration
(leading to irreversible blindness), cataracts, menopausal symptoms,
insomnia, diminished memory and concentration, digestive upsets and
constipation and not to mention headaches. Nutraceuticals are marketed
in concentrated forms as pills, capsules, powders and tinctures either as
a single substance or as combination preparations.

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Categories of Nutraceuticals
Nutraceuticals are non-specific biological therapies used to promote
wellness, prevent malignant processes and control symptoms. These
can be grouped into the following three broad categories:
1. Substances with established nutritional functions, such as
vitamins, minerals, amino acids and fatty acids – Nutrients
2. Herbs or botanical products as concentrates and extracts – Herbals
3. Reagents derived from other sources (e.g., pyruvate, chondroitin
sulphate, steroid hormone precursors) serving specific functions,
such as sports nutrition, weight-loss supplements and meal
replacements- Dietary supplements.

Nutrients:
The most commonly known nutrients are antioxidant, water and fat-
soluble vitamins. Many potential benefits have been attributed to
antioxidant use in the form of dietary intake or supplementation.
Antioxidants, in general, may be useful in the prevention of cancer
and cerebrovascular disease. High dietary intake of vitamin E may
prevent Parkinson’s diseases. Agus et al., determined that the oxidized
form of vitamin C, dehydroascorbic acid, readily crosses the blood
brain barrier.
These findings have implications for increasing the uptake of
antioxidants in the central nervous system; thus, some feel that this
has the potential for improving the treatment of Alzheimer’s
disease. Jialal and Fuller found that the combination of vitamin E, C
and beta carotene has been useful in reducing low density
lipoprotein oxidation and subsequent athero- sclerosis. Vitamin
supplement is associated with increased antibody titre response to
both hepatitis B and tetanus vaccines as a result of macrophage and
T cell stimulation. Those genetically predisposed to pancreatic
cancer have low serum levels of selenium, thus, it is assumed that
supplementations selenium may help to prevent this condition
Those suffering from asthma and skin cancer have also been
evaluated with selenium for its potential use, although results have
been inconclusive Zinc is an essential component of more than
hundred enzymes involving digestion, metabolism and wound
healing. L-arginine is a semi-essential amino acid that is a substrate
for nitric oxide production. Ceremuzynski demonstrated that
supplementation of L-arginine improved exercise capacity in
patients, who had angina. A list of common nutrients with their
health benefits.

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Herbals:
Herbals are as old as human civilization and they have provided a
complete storehouse of remedies to cure acute and chronic diseases.
The knowledge of herbals has accumulated over thousands of years so
that today we possess many effective means of ensuring health care.
Numerous nutraceuticals are present in medicinal herbs as key
components. A list of commonly known herbal and phytochemical
products with their therapeutic activity. Herbal extracts, including β-
sitosterols (found in Saw Palmetto berry), cernilton (pollen extract),
and pygeum africum (African plum) have been clinically evaluated for
use in the treatment of benign prostatic hyperplasis. It has been found
that common herbal treatment is in the use of Echinacea for the
prevention and treatment of colds and flu. A series of five placebo-
controlled studies evaluating the use of Echinacea produced mixed
results, which the authors attribute to either the use of healthy
volunteers, rather than patients, or the use of extracts that were not
standardized or chemically defined mono- preparations. Ernst
suggested that St John’s wort is efficacious for mild to moderate
depression, but serious concern exists about its interactions with
several conventional drug. Echinacea may be helpful in the treatment
or prevention of upper respiratory tract infections, but trial data are not
fully convincing. Saw Palmetto has been shown in short term trials to
be efficacious in reducing the symptoms of benign prostate
hyperplasia. Kava is an efficacious short-term treatment for anxiety.
None of these herbal medicines free of adverse effects. St. John’s Wort
extract only instance, interacts with prescription drugs leading to
potentially serious consequences.It is a mild monoaminoxidase inhibitor
and cannot be used with high tyramine foods and antidepressants. A
case describes a kidney transplant patient whose cyclosporin level
dropped dramatically and dangerously after self-medicating St. John’s
wort extract at only one-third of the recommended dose. It was
suggested that gingko is of questionable use for memory loss and
tinnitus but has some effect on dementia and intermittent claudication.
The increase in microcirculation observed with ginkgo may be a
mechanism of the improvement of cognitive function seen in healthy
individuals and those with dementia. A positive effect of Ginkgo biloba
on cognitive function is not proven by data from rigorous clinical trials.
The use of Ginkgo biloba as a “smart" drug cannot be recommended on
the basis of the evidence available to date and there is a particular need
for further long-term trials with healthy subjects. Vegetables, fruits,
whole grains, herbs, nuts and seeds contain an abundance of phenolic

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compounds, terpenoids, sulfur compounds, pigments, and other natural

antioxidants that have been associated with protection from and/or
treatment of conditions such as cardiovascular disease and cancer. The
foods and herbs with the highest anticancer activity include garlic,
soybean, cabbage, ginger, liquorice root and the umbelliferous
vegetables. Citrus, in addition to providing an ample supply of vitamin
C, folic acid, potassium, and soluble fibre, contains a host of active
phytochemicals. Clinical trials have not yet been able to demonstrate
the claimed protective effects from taking supplement. Epidemiological
and experimental studies suggest that dietary phytosterols may offer
protection from the most common cancers in Western societies, such as
colon, breast and prostate cancer. The possible mechanisms by which
phytosterols offer this protection include the effect on membrane
structure and function of tumor and host tissue, signal transduction
pathways that regulate tumor growth and apoptosis, immune function of
the host and cholesterol metabolism by the host. Silagy and Neil
suggested that garlic powder preparation might be of some clinical use
in subjects with mild hypertension. However, there is still insufficient
evidence to recommend it as a routine clinical therapy for the treatment
of hypertensive subjects. Garlic is superior to placebo in reducing total
cholesterol levels. However, the size of the effect is modest and the
robustness of the effect is debatable. The use of garlic for
hypercholesterolemia is therefore of questionable value. The possible
protective effect of aqueous garlic extract against oxidative organ
damage distant from the original burn wound was determined. Burn
injury caused a significant decrease in glutathione level and significant
increases in malondialdehyde and protein oxidation levels and
myeloperoxidase activity at post-burn 2 and 24 h. Since garlic extract
reversed these oxidant responses it seems likely that garlic extract
protects tissues against oxidative damage. The infusion of pig growth
factor-mobilised peripheral blood leukocytes (containing 1 to 2%
progenitor cells) (pPBPC) into baboons is associated with a thrombotic
microangiopathy which results from a direct effect of these pig cells on
platelet aggregation. Adjoin is a synthetic derivative of garlic that
inhibits aggregation of human platelets induced by all known agents.
Although adjoin is a powerful inhibitor of platelet aggregation, the need
for repeated administration and its partial effect on pPBPC- induced
platelet aggregation would suggest that it may be of only limited value
in preventing the thrombotic microangiopathy that develops when
pPBPC are infused into baboons. Compounds like diallyl sulphides,
diallyl disulphides and quercetin which are active components of garlic,
have known anti-inflammatory, antimutagenic activities. Similarly,

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active components in tomato, such as kaempferol and chlorogenic acid,

have antimutagenic activities and lycopene is the most active oxygen
quencher with potential chemo preventive activities. These results
suggest that tomato and garlic suspensions have a protective effect on
colon carcinogenesis which is mediated by modulation of different
biological pathways during carcinogenesis.
Honey has proven antimicrobial activity. Green tea enhances humoral
and cell mediated immunity while decreasing the risk of certain cancers
and the risk of cardiovascular disease. Ginseng enhances production of
macrophages, B and T cells, natural killer cells and colony- forming
activity of bone marrow. Panax ginseng prevents irradiation- induced
programmed cell death in hair follicles, suggesting important
therapeutic implications.
Nutraceuticals (dietary plants) like soya bean, garlic, ginger and green
tea which have been suggested, in epidemiological studies, to reduce
the incidence of cancer may do so by inducing programmed cell death.
Soybean extract has been shown to prevent development of disease like
polycystic kidneys, while Artemisia asiatica attenuates cerulein-
induced pancreatitis in rats. Interestingly enough, a number of food
items as well as herbal medicines have been reported to produce toxic
effects by inducing programmed cell death. Four nutraceuticals, sugar
beet roots, cucumber fruits, New Zealand spinach leaves and turmeric
rhizomes, were evaluated for their comparative effectiveness against
dimethylbenz (a)anthracene- initiated and croton oil-promoted skin
tumours and found that turmeric is the most potent nutraceutical against
such tumours.
Scientific evaluation of herbal products has been limited, yet herbal
products are the most commonly consumed health care products.
Because of known pharmacological effects and potential interaction of
many of these compounds with therapeutic drugs, a history of herbal
intake should be considered as part of routine medical history and
should be evaluated before any change in prescription drugs and before
medical procedures.

Dietary supplements:
Dietary supplements have also been developed to manage a variety of
diseases. For instance, pre-packaged, nutritionally balanced meals that
meet the recommendations of national health organizations influenced
multiple risk factors for patients with cardiovascular disease and
increased patient compliance with dietary restrictions. Ketogenic diets,
comprised of foods high in fat and low in protein and carbohydrate

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content, have been reported to improve seizure control. However, these

diets are widely acknowledged to be unpalatable, making sustained
compliance with dietary restrictions difficult Cereals and grains is an
area of nutraceuticals in which calcium fortification is very strong.
Kellogg’s is a leader with calcium fortified All-Bran plus and
Nutrigrain bars.
Researchers have found that minimally refined grains may reduce the
incidence of diabetes and may be beneficial in the prevention of
gastrointestinal cancers.
Burgeon is bread containing soya flour and linseeds, which provide
phytoestrogens, natural substances that mimic the structure of hormone
oestrogen.
Phytoestrogens have been documented to enhance oestrogen levels
when hormonal levels are low or to weaken the effects of oestrogen
when levels are high. This action may prevent against both hot flushes
and breast cancer. Other common foods that may have potential
therapeutic value include edible mushrooms. For example, several
species of edible mushrooms in order of decreasing cultivated tonnage,
Lentinus (shiitake), Pleurotus (oyster), Auricular (mu-er), Flammulina
(enokitake), Tremella (yin-er), Hericium, and Grifola (maitake) have
varying degrees of immunomodulatory, lipid lowering, antitumor and
other beneficial or therapeutic health effects without any significant
toxicity.
Zbar and NiteBite are two products in the form of bars that contain
sucrose, protein and uncooked starch in order to provide continuous
glucose release to diabetics during the night.
The sucrose is released immediately while the protein is converted to
glucose approximately 2- 5 hours after ingestion and the uncooked
starch is converted to glucose 6-8 h post Ingestion.
Stableman found a novel and exciting application of egg technology by
using the egg antibodies to prevent or treat diseases. The two
nutraceuticals namely glucosamine sulphate and chondroitin sulphate
are effective and safer to alleviate symptoms of osteoarthritis whereas
Deal and Moskowitz emphasised that glucosamine sulphate and
chondroitin sulphate are not FDA-evaluated or recommended for
treatment of osteoarthritis.
Immune milk products are promising examples of health promoting
nutraceuticals. Numerous casein and whey protein derived angiotensin-
I- converting enzyme inhibitory peptides/hydrolysates have been
identified.
These peptides/ hydrolysates may be classified as nutraceuticals due to
their ability to provide health benefits. Buckwheat has been used and
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will be better used as an important raw material for functional food

production. Buckwheat proteins have unique amino acid composition
with special biological activities of cholesterol- lowering effects, anti-
hypertension effects and improving constipation and obesity by acting
similar to dietary fiber and interrupting the in vivo metabolism. The
trypsin inhibitor isolated from buckwheat seeds are heat stable and can
cause poor digestion if they are not suitably cooked before
consumption. The buckwheat seeds may also contain some allergenic
proteins, which induces allergy. Buckwheat flour can improve diabetes,
obesity, hypertension, hypercholesterolemia and constipation. An
emerging area of nutraceuticals is that of dairy foods containing
friendly or probiotic bacteria claimed to promote gut health. Bio
yoghurts containing Lactobacillus acidophilus and Bifidobacteria lead
the sector; whilst specialist fermented products such as yakut
(providing L casei Shirota), nestles LC1 (providing Lactobacillus
johnsonii) and the culturelle (providing Lactobacillus GG) are also
strong players. Drinks are a fast-developing area of functional foods. A
new range of herb enhanced drinks called Phuse claims to help
overcome problems ranging from postmenstrual syndrome to lack of
energy.
Recently, Mei et al. prepared calcium caseinate and whey protein
isolate films and found that these films may be used for wrapping or
coating to enhance the nutritional value of foods.
Because of these findings, nutraceuticals are becoming more widely
accepted as an adjunct to conventional therapies for enhancing general
well-being. As a result of extensive research on these nutraceuticals
various products are available in National and International market.

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Area of concern
The lack of quality control is a major area of concern for nutraceuticals.
The quality of plant material and manufacturing processes used for
nutraceuticals are regulated by food laws, which lack the specificity
required for botanical drugs. This can have serious consequences.
Contamination, for instance, with toxins after fungal infection of raw
plant material or with other ingredients has been repeatedly reported
and can have potentially fatal consequences.
Adulterations and numerous other types of impurity of nutraceuticals
conceivably remain undetected simply because there is an almost total
absence of specific quality control. Absence of quality control not
only increases the risk to the consumer; it also results in a total lack of
impetus to conduct adequate research that demonstrates the potential
benefits of nutraceuticals or ensures their safety.
New clinical applications of nutraceuticals are increasingly being
reported, but there are fundamental differences between formulation,
production and the evidence supporting clinical use. Nutraceuticals
generally fall within the novel foods and ingredients regulations but
their purity, dosage requirements and clinical consequences exceed
those of most ‘health- foods’. Replacement of one nutrient or
antioxidant is unlikely to correct the cascade of interconnected
metabolic abnormalities associated with many diseases. Cost is
another factor that receives scant attention. These products sell for
substantial amounts more than mainstream products, in as much as
botanicals are costly to produce.

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Regulatory aspects
In USA, watershed legislation was passed in 1994 to regulate the
manufacture and marketing of nutraceuticals. This law, known as the
Dietary Supplement Health and Education Act, reversed 45 years of
increasing FDA regulation of health-related Products. The FDA may
establish good manufacturing practices for nutraceuticals as long as
these regulations are molded after the less stringent regulations for
foods as opposed to those for drugs. A draft law reminiscent of the
Dietary Supplement Health and Education Act is in development in
India to regulate manufacturing, importing and marketing of health
foods/dietary supplements and other nutraceuticals. Also, the country's
central drug control department has put some structures in place for
dietary supplements, but it is taking a long time for states to cooperate
and some states have rejected the structures when their own rules and
regulations conflict. Also, a new independent association has been
formed in India to address some of these issues. The Indian Health and
Dietary Supplement Association was created to represent
pharmaceutical, nutraceutical, herbal, direct selling and other service-
oriented industry companies and plans to affiliate with the International
Alliance of Dietary Supplement Associations in the near future. The
association is planning a scientific conference to bring the industry and
government together to share information,
experience and perspectives on the use and regulation of dietary
supplements.

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Management of Nutraceuticals

Management of Osteoarthritis
Osteoarthritis (OA) is one of the most prevalent and disabling chronic
diseases affecting older people. A high prevalence of OA among older
people and women and the moderate to severe impact on daily life pose
a significant public health problem. OA involves the erosion of
articular cartilage, inflammation of synovial membrane, and resorption
of the underlying subchondral bone. These pathological changes are
associated with an excessive production of pro-inflammatory
molecules such as interleukin 1β (IL-1β) and tumor necrosis factor α
(TNFα), which shift the balance between the synthesis and degradation
of matrix components resulting in progressive destruction of the joint
tissue.
Today, a cure for OA remains elusive. Nonpharmacological
management includes physical therapy, aerobic exercises, muscle
strengthening, weight reduction, walking aids, knee braces, footwear
and insoles, electromagnets, thermal modalities and acupuncture. For
OA treatment and prevention, glucosamine and chondroitin sulfate, two
of the molecular building blocks found in articular cartilage, are the
most commonly used dietary supplements. In randomized trials of
variable quality, these compounds show efficacy in reducing symptoms,
but neither has been shown to arrest progression of the disease or
regenerate damaged cartilage. Pharmacological management of OA has
targeted symptoms of the disease rather than the underlying cause;
analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)
represent the mainstay of treatment. These drugs generally decrease pain
and stiffness and improve function. Although, any beneficial effects to
the underlying cartilage and bone associated with the use of these drugs
have not been demonstrated, they remain among the most widely
prescribed drugs for OA therapy.
Other treatment options are selective cyclooxyrgenase 2 (COX-2)
inhibitors (rofecoxib) for pain management but these drugs are reported
to be associated with gastrointestinal and cardiovascular adverse events.
Matrix metalloproteinase (MMP) inhibitors have been studied for
prevention of cartilage degradation but their clinical use has been
limited by severe side effect. Intra-articular therapies like glucocorticoid
and hyaluronan injections have been used for pain relief but recent
observations suggest that they may accelerate cartilage breakdown.
Basically, long- term use of available pharmacological agents to relieve

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

OA symptoms is associated with serious adverse events and highlights

the importance of developing safer alternative and prevention strategies.
Such prevention and alternative/adjunct therapies could come from
nutraceuticals. The term ‘nutraceutical ’was coined from ‘nutrition ’and
‘pharmaceutical ’in 1989 by DeFelice and was originally defined as ‘a
food (or part of the food) that provides medical or health benefits,
including the prevention and/or treatment of a disease. Zeisel
distinguished whole foods from the bioactive chemical compounds
derived from them and available in a nonfood matrix by using the terms
‘functional foods ’and ‘nutraceuticals’ respectively. However, the term
nutraceuticals have no regulatory definition and is not recognized by the
US Food and Drug Administration (FDA), which uses the term ‘dietary
supplements ’instead OA as a chronic disease is a perfect paradigm of
pathology of treatment, which could be addressed by nutraceuticals and
dietary supplements. First, because nutraceuticals only have limited
effects on their biological target and significant differences can be
reached over time through a buildup effect in which daily benefits add
up and the time window for intervention is longer in chronic diseases.
Second, nutraceuticals could provide a safer alternative because
generally their use is devoid of adverse effects, although this is not
universal. Public interest in the benefits provided by nutraceuticals such
as medicinal herbs for OA is high and 47% of older adults use non-
prescribed alternative medications (dietary supplements) for OA
management. The objective of this review is to discuss the scientific
evidence supporting the efficacy of Punica granatum (pomegranate
fruit), Camellia sinensis (green tea), Uncaria tomentosa/Uncaria
guianensis (cat’s claw), Harpagophytum procumbens (devil’s claw),
Zingiber officinale (ginger), Boswellia serrate, Curcuma longa
(turmeric) and Ananas comosus in an attempt to understand the pivotal
molecular targets involved in inflammation and the joint destruction
process and to summarize their toxicities and efficacies for OA
management.
We have purposely not considered use of glucosamine sulphate
and chondroitin sulphate because these compounds have been the
main topic of numerous knowledge. For this review a literature
search was performed of the Pubmed database and the scientific
data with a direct link to OA were selected. We tried to include
all the relevant references but the list may not be complete. If
some published work is not included, the omission is
unintentional.

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Punica granatum (pomegranate)

Pomegranate fruit has been used for centuries to confer health benefits
in many cultures. It is native to semitropical Asia and is now being
cultivated in Afghanistan, India, China, Russia, Japan and the United
States. Modern use of PF- derived products includes treatment of
AIDS, cancer, cosmetic use, allergic symptoms, cardiovascular
conditions, oral hygiene and as ophthalmic ointment. Edible parts of
the PF are composed of 80% juice and 20% seed PF itself is a rich
source of two types of polyphenolic compounds: anthocyanins (such as
delphinidin, cyanidin, and pelargonidin) and hydrolyzable tannins
(such as punicalin, pedunculagin, punicalagin, gallagic, and ellagic acid
esters of glucose), which account for 92% of the antioxidant activity of
the whole fruit.
Anthocyanins are potent antioxidants, provide the brilliant color of the
pomegranate juice, and their administration is reported to significantly
decrease the malondialdehyde, hydroperoxide levels, lipid peroxidation
and also enhance the activities of catalase, superoxide dismutase,
glutathione peroxidase and glutathione reductase in the liver.
Punicalagin has been shown to downregulate the expression of IL-2
from anti- CD3/anti-CD28-stimulated murine splenic CD4+ T cells and
suppress mixed leukocyte reaction without exhibiting cytotoxicity to the
cells via inhibition of nuclear factor of activated T cells. This suggests
that PF could be a potential candidate for the therapeutics of immune
pathologies. We reported that pomegranate fruit extract (PFE)-derived
bioavailable compounds suppress COX-2 enzyme activity and IL-1β-
induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in
OA chondrocytes. We showed the inhibitory effects of PFE on IL-1β-
induced proteoglycan breakdown in cartilage explants in vitro. We also
studied the efficacy of PFE in suppressing joint inflammation and
damage using a collagen-induced arthritis mouse model. Consumption
of PFE potently delayed the onset and reduced the incidence of
collagen-induced arthritis in mice. Histopathology of the arthritic joints
from PFE-fed mice demonstrated reduced joint.
infiltration by the inflammatory cells, and the destruction of bone and
cartilage was alleviated with the decrease level of IL-6. Activation of
mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB is
intimately associated with the increased expression of critical mediators of
inflammation involved in OA pathogenesis, including the expression of IL-6
and IL-8. We recently showed that inhibition of IL-6 and IL-8 by PFE in
PMACI phorbol-12- myristate 13-acetate plus calcium inophore A23187-
stimulated KU812 cells was mediated by inhibition of NF-κB, cJun-N-

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terminal kinases and the extracellular regulated kinase pathway. We also

showed that PFE (6.25–25 mg/litre) inhibits the IL-1β-induced expression of
MMP- 1, MMP-3 and MMP-13 mRNA and proteins in OA chondrocytes,
which was mediated by inhibiting the activation of p38-MAPK and JNK,
thereby reducing the available pool of activated c-Jun and activating
transcription factor. Our recent study showed that PFE inhibits the IL-1β-
induced isoform and DNA binding activity of the runt-related transcription
factor 2 in human chondrocytes. These results provide an important insight
into the molecular basis of the reported cartilage protective and arthritis
inhibitory effects of pomegranate.

Camellia sinensis (green tea)

Tea is a widely consumed beverage throughout the world and is
reported to possess significant health-promoting effects (reviewed by
Cabrera and colleagues and reference therein) Green tea contains
proteins (15%), amino acids (4%), fiber (26%), other carbohydrates
(7%), lipids (7%), pigments (2%), minerals (5%), and phenolic
compounds (catechin; 30%). The principal catechin found in green tea
are epicatechin (6.4%), epicatechin-3-gallate (13.6%), epigallocatechin
(19%) and epigallocatechin -3- gallate (EGCG; 59%), and account for

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

30–40% of its dry weight.Green tea catechin, especially EGCG, have

been reported to have antimutagenic , anticancer anti diabetic , anti-
inflammatory antibacterial antiviral, anti-obesity and neuroprotective
effects. The strong antioxidant activity of green tea catechin has been
widely demonstrated in vitro and in vivo.
Several studies have shown that EGCG blunts reactive oxygen species
(ROS)-mediated cytotoxicity in human chondrocytes. EGCG has been
reported to increase the activities of catalase, superoxide dismutase, and
glutathione peroxidase, which are essential components of a robust
antioxidant defence system.The potential disease-modifying effects of
green tea on arthritis came to light through our study, when in a mouse
model of rheumatoid arthritis (RA) induction and severity of arthritis
was ameliorated by the prophylactic administration of green tea
polyphenols in drinking water. The anti-inflammatory and antiarthritic
effects of EGCG are supported by several studies, indicating that green
tea or its component EGCG can regulate the expression of cytokines,
chemokines, MMPs, aggrecanase, ROS, NO, COX-2, and PGE2 in cell
types relevant to the pathogenesis of OA. We recently studied the global
effect of EGCG on IL-1β-induced expression of cytokines and
chemokines associated with OA pathogenesis in human chondrocytes.
Our results suggest that the potential of EGCG in OA treatment and
prevention may be related to its ability to globally suppress the IL-1β-
induced inflammatory response in human chondrocytes. Similarly,
others have shown the inhibitory effects of EGCG on IL-1β, TNFα, IL-
6, regulated upon activation normal T-cell expressed and secreted
(RANTES), monocyte chemotactic protein 1, epithelial neutrophil
activating peptide-78, and growth-related oncogene α expression in RA
synovial fibroblasts and other cell types. NF-κB and MAPKs are
involved in the regulation of genes important in high expression of
several mediators of inflammation in OA. EGCG has been reported to
downregulate IL-6 expression by inducing alternative splicing of gp130
mRNA resulting in enhanced sgp130 production in RA synovial
fibroblasts. High levels of nitrates/nitrites have been found in the
synovial fluid and serum of patients with OA. Studies from our
laboratory have shown that EGCG inhibits NO production in IL-1β-
stimulated human OA chondrocytes by suppressing the expression of
inducible nitric oxide synthase (iNOS) mRNA, which was mediated in
part by inhibition of NF-κB/p65. COX-2 is the rate limiting enzyme in
the production of PGE2 and we reported that EGCG inhibited the PGE2
production via inhibition of COX-2 expression in IL-1β-stimulated
human OA chondrocytes.
However, Koeberle and colleagues reported that microsomal

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prostaglandin-E synthase 1 (mPGES-1) is a molecular target of EGCG,

and inhibition of mPGES-1 is seemingly the predominant mechanism
underlying suppression of cellular PGE2 biosynthesis by EGCG in vitro.
Age-related accumulation of advance glycation end products (AGEs)
produced by the non-
enzymatic glycation of macromolecules could be an important
contributing factor for the development of OA. We recently reported
that EGCG inhibited AGE-stimulated expression and production of
TNFα and MMP-13 and this inhibitory effect was mediated at least in
part via suppression of p38-MAPK, JNK, and NF-κB activation in
human OA chondrocytes. EGCG has also been reported to inhibit the
degradation of human cartilage proteoglycan and type II collagen and
selectively inhibit the expression of ADAMTS-1, -4 and -5, which are
known to cleave aggrecan.

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NUTRACEUTICAL AND CANCER

MANAGEMENT

Cancer:
Cancer is a group of diseases involving abnormal cell growth with the
potential to invade or spread to other parts of the body. These contrast
with benign tumors, which do not spread.

Nutraceuticals in Cancer
Cancer is a growing health problem around the world particularly with
the steady rise in life expectancy, increasing urbanisation and the
subsequent changes in environmental conditions and lifestyle. It has
been suggested by several studies that frequent consumption of
vegetables and fruits decreases the risk of colon cancer, the third most
common cancer in both men and women
1. Diet, high intake of grains, legumes, fruits, vegetables and other
edibles rich in phytoestrogens
2. high-fiber
3. low- fat diet
4. have their own importance in preventing colon cancers and others
like breast
5. prostate
6. lung cancer
7. Which are more prevalent in the developed countries?
8. Dietary components may prevent cancer from reaching its invasive
and metastasis stages or they may reduce the risk of secondary
complications or modify the behavior of established cancer.
According to a recent report, functional foods represent an exploding
market, an estimated value of $29 billion a year, in the United States
alone. The food industry is pouring millions of dollars into this
transformation, and if the health claims on these products, prove to be
true and the food is tasty, they may succeed. It is expected that over the
next few years "there will be a glut of foods, designed to optimize
health, and that supermarkets of the future will have entire sections set
aside for the prevention of chronic illnesses.
In addition to the nutrients, human diets of plant origin contain hundreds
of compounds which may not be considered as nutrient. However, they
play an important role in the maintenance of health. Traditional systems
of medicine in different countries are practicing these herbs for health
management since centuries, but in most of the cases, claims are not

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scientifically validated. This seems to be one of the main reasons, why

these herbal food supplements are not in use as it should be, by the
suffering humanity. Therefore, keeping in view the pressing demand of
alternative medicine, especially for the chronic disorders, World Health
Organization (WHO) and National Institute of Health (NIH), USA have
taken it as a mission to validate the claims of these medicinal plants and
to develop them as a safe, scientifically proven food supplement. This
review focuses some of the past researches, establishing the role of
medicinal plant products in cancer management. This will help the
readers to plan the future experiments in this field.

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ETIOLOGY OF CANCER
Carcinogenesis results from the accumulation of multiple sequential
mutations and alterations in nuclear and cytoplasm molecules,
culminating to invasive neoplasms (12). These events can be divided
into three phases: initiation, promotion, and progression. Initiation is a
rapid process, involving carcinogen binding to the target and DNA
damage (13). In the promotion phase, which is generally reversible,
tumor promoters, acting as mitogens, induce clones of initiated cells to
expand. Promotion is a consequence of the functional loss of regulatory
proteins and cellular check points, important for proliferation and
apoptosis. Progression defines the stage in which phenotypically and
genotypically altered cells develop irreversible macroscopic changes.
Both promotion and progression phases are of long duration, probably
of many years. This model allows a convenient classification of chemo-
preventive agents to the groups that can block initiation or suppress
promotion and progression.

NUTRACEUTICALS AND CANCER

The plant products have been defined as food, food supplement,
functional food and nutraceuticals, depending upon its isolation step.
Pure extracted phytomolecule is named as nutraceuticals, whereas
semi- purified plant product, not taken as regular food, is named as
functional food (16). Food supplements are those products which can
be taken regularly as food to maintain the general health. Plant foods
contain a variety of components including micronutrients,
polyunsaturated fatty acids, and secondary metabolites such as
glucosinolates, flavonoids, polyphenols, phytoestrogens,
phytosterols, lignans, terpenes, phytates etc. Functionally they may
be classified as dietary fiber, antioxidants, detoxifying agents,
immunity-potentiating agents and neuropharmacological agents, with
variety of chemicals with differing potency.

PHYTOCHEMICALS WITH ANTI-CANCER

PROPERTIES
Nutritional modulation may be beneficial in the treatment of cancer
patients. There is evidence that foods, relatively low in simple
carbohydrates with moderate amounts of high- quality protein, fiber, and
fat (especially fats of the omega-3 fatty acid series) are beneficial for
cancer patients. In addition, certain supplemental micronutrients,

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nutraceuticals and functional foods may have potential to reduce the risk
of developing cancer, or retarding the rate of growth and metastases of
established malignant disease. It may also be helpful in reducing
toxicity, associated with chemotherapy and radiation therapy, and may
lead to better life conditions by reducing cancer cachexia. They may
inhibit cell proliferation and induce apoptosis in the cancer cells. The
phytochemicals have shown different mechanism of actions at different
cellular levels. Most of them have emerged as a versatile source of
antioxidants and there by affecting the signaling pathway related to
redox mediated transcription factors. Besides, they directly modulate the
endocrine system, immunological cascade and enzymes related to
inflammation.
Some of them have shown direct effect on DNA repair and cleavage
process.

POSSIBLE MECHANISMS OF ACTION OF

NUTRACEUTICALS AS CHEMO-PREVENTIVE
AGENT
Chemoprevention can be defined as the use of natural or synthetic
chemicals to reverse, suppress, or to prevent the process of
carcinogenesis. Solid cancer in early stage, are generally detected as
intraepithelial neoplasia or carcinoma in situ, which correspond to the
promotion and progression stages. Therefore, anti-promotion ’and ‘anti-
progression ’agents may be of particular clinical interest. Ultimately,
such agents prevent the growth and survival of cells already committed
for malignancy.
Bioactive substances in a dietary compound, even in very low
concentrations, may have a far greater impact than previously
appreciated on the regulation of gene expression. Continuing research
on the effects of nutraceuticals on gene expression should provide
insight into the mechanisms of prevention of diseases such as obesity,
diabetes, atherosclerosis, hypertension and cancer by dietary
manipulations. A few current studies on the action of selected
nutraceuticals on the activity of transcription factors such as activator
protein (AP-1), including nuclear factor kB (NFkB), sterol response
element binding proteins (SREBPs), peroxisome proliferator-activated
receptor- gamma (PPARgamma), modulation of the expression of
antioxidant genes like Bcl- 2 as final targets in the signal transduction
cascade and gene regulation, have paved a path to further investigate
these molecules in a great detail, using various genetic diseased animal
models.

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CANCER CACHEXIA AND FOOD SUPPLEMENT

Besides the active role of nutraceuticals and functional foods in the
control of cancer progress, there is also a great need to develop the food
supplements as the add-on therapy to provide better quality of life for a
cancer patient. They usually show cancer cachexia, which may be
defined as significant alterations in their carbohydrate, protein and fat
metabolism, resulting to bad quality of life, reduce response to therapy,
and shorten survival span. Nutritional modulation may be beneficial in
the treatment of cancer patients to reverse these metabolic alterations.
Although foods with relatively low carbohydrates, moderate high-
quality protein, fiber, and fat rich in omega-3 fatty acid series is
considered to be beneficial for such patients.
However, certain medicinal plants, especially acting on the liver and
gastrointestinal system, may prove to be better food supplement in
improving the quality of life. Nutritional intervention can be a powerful
tool for controlling malignant disease and for reducing toxicity
associated with chemotherapy and radiation therapy.

FAT AND CANCER

Low fat and high fiber diets can further enhance the efficacy of standard
cancer therapeutic agents; (46) the proposed mechanisms for these
effects include the production of increased levels of butyric acid (47)
and binding of potential mutagens in the gastrointestinal tract by high
fiber and reduced levels of growth promoting agents such as
prostaglandins, certain fatty acids and estrogen by low fat. Functional
foods relatively low in soluble carbohydrate; moderate amounts of
protein that includes sources of arginine, and moderate amounts of fat
supplemented with omega-3 long-chain polyunsaturated fatty acids have
been shown to be beneficial. Other nutraceuticals of interest in patients
with cancer include antioxidant vitamins, trace minerals, glutamine,
protease inhibitors, garlic and tea polyphenols.

NUTRACEUTICALS AND IMMUNE MODULATION

Nutraceuticals can significantly raise natural killers’ cell (NK cell)
function and tumor necrosis factor (TNFa) in patients with late-stage
cancer.
An aggressive combination of immuno-active nutraceuticals has been
suggested to be effective in significant improvement in NK cell
function, other immune parameters and hemoglobin in patients with
late-stage cancers.

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MEDICAL PLANTS IN APOPTOSIS

Programmed cell death (apoptosis), has generated considerable interest
in recent years. It is a highly conserved mechanism of self- defence.
Both extra-cellular signals and intracellular events have been associated
to this event. Enhancement of apoptosis may reduce the cancer growth
as this process is down regulated in cancer tissues. Recently, a variety of
plant extracts have been investigated for their ability to influence the
apoptotic process such as Rubia cordifolia, Semicarpus anacardium,
isolated compounds like bryonolic acid (from Trichosanthes kirilowii
var. Japonica, crocin (from saffron) and allicin (from Allium sativum).
Several mechanisms have been identified to underlie the modulation of
programmed cell death by plants including endonuclease activation,
induction of p53, activation of caspase 3 protease via a Bcl-2-
insensitive pathway, activation of free-radical formation and
accumulation of sphinganine.

CURCUMIN
Curcumin is known to induce apoptosis malignant cell lines by
suppressing a number of key elements in cellular signaling pathways
pertinent to growth, differentiation and malignant formation. It is one
of the extensively investigated phytochemical, with regard to
chemopreventive potential. It inhibits the TNF-a induced COX-2
transcription and NFkB activation by inhibiting the IkB degradation,
through down regulation of NFkB inducing kinase (NIK) and IkB
kinase. Curcumin inhibited the catalytic activity of ERK 1/2 in
different cell systems (100). Alternatively, curcumin acts through
another transcription factor NRF2, which normally exits in an inactive
state as a consequence of binding to KEAP1 protein. Curcumin is
unstable at neutral and basic pH and more than 90% of curcumin
decomposes rapidly in buffer systems at this pH. It gets degraded to
ferulic acid ([4- hydorxy-3-methoxy cinnamic acid)] and feruloyl
methane (4-hydroxy-3- methoxycinnamoyl methane).

VITAMINS AND MINERALS IN CANCER

MANAGEMENT
The role of vitamins A, C, E and trace elements like selenium has been
suggested to prevent cancer in several independent studies. Its action
may be through the modulation of immune function or through
antioxidant properties or by direct effect such as inhibition of N-
nitrosamine formation or cell-to-cell interactions and modulation of the

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enzyme activity. It may be important for the patients undergoing

chemotherapy and radiotherapy because in that stage, requirement for
antioxidant compounds increases. Thus, supplementation with
micronutrients as adjuvant in cancer patients may prove to be helpful
(110).
Antioxidant, vitamin and minerals are always protective to the cancer as
they protect the DNA damage from the free radical attack and Cancer is
a disease of the genome. Several epidemiological studies have
suggested the role of diets rich in fruits and vegetables in cancer
protection. Individual antioxidants such as vitamin A (retinoids),
vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily
sodium ascorbate) and carotenoids (primarily polar carotenoids) induce
cell differentiation and growth inhibition to various degrees in rodent
and human cancer cells by complex mechanisms. The suggested
mechanisms for these effects include the inhibition of protein kinase C
activity, prostaglandin E1- stimulated adenylate cyclase activity,
expression of c-myc, H-ras, and a transcription factor (E2F), and
induction of transforming growth factor-beta and p21 genes. Besides,
these vitamins may enhance the anti-tumor effects of x- irradiation,
chemotherapeutic agents and hyperthermia thereby acting as biological
response modifiers. They also reduce
the toxicity of several standard tumor therapeutic agents in normal cells.
Selenium has been associated with several positive benefits related to
chronic diseases, ageing and cancer.
Similarly, bee honey and Nigella grains have shown significant
protection against oxidative stress and carcinogenesis (80%) induced by
methylnitrosourea (MNU) in rats.

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NUTRACEUTICALS MANAGEMENT IN
DIABETES MELLITUS
Diabetes Mellitus is a complex metabolic disorder associated with
developing insulin resistance, impaired insulin signalling and β-cell
dysfunction, abnormal glucose and lipid metabolism, sub-clinical
inflammation and increased oxidative stress; It was estimated to affect
2.8% of the worldwide population in the year 2000, and it is expected
to affect 4.4% in 2030 due to the population ageing and a constant
increase in obesity; these metabolic disorders lead to long-term
pathogenic conditions including micro-vascular and macro-vascular
complications, neuropathy, retinopathy, nephropathy, and a consequent
decrease in quality of life and an increase in the rate of mortality.1‒3
Among the multiple risk factors underling the incidence and
progression of type 2 diabetes mellitus, diet is the main modifiable
factor. An increasing number of epidemiological investigations show
that diet rich in foods with high content of phytochemicals, high total
antioxidant capacity and polyphenolic compounds may be related to
lower risk of diabetes and predisposing factors.Based on the current
understanding of pathophysiology of insulin resistance and type 2
diabetes mellitus, multiple pharmacological and non- pharmacological
interventions have been developed with the aim of improving glycemic
control and prevention of diabetes complications; in this area, recently
the use of functional foods and their bioactive components have been
considered as a new approach in the prevention and management of
diabetes and its complications. A nutraceutical is a food with a
medical-health benefit, including the prevention and treatment of
disease. Nutraceuticals also refer to natural functional/medical foods or
bioactive phytochemicals that have health promoting, disease
preventing or medicinal properties.
These nutraceuticals normally contain the required amount of vitamins,
lipids, proteins, carbohydrates, minerals, or other necessary nutrients,
depending on their emphases. Traditional medicinal plants are used
throughout the world for a range of diabetic presentations.
Herbal drugs are prescribed widely because of their effectiveness, less
side effects and relatively low cost. Therefore, investigation on such
agents from traditional medicinal plants has become more important.
The present review, deals with some selective Herbal medicinal plants
having pharmacologically established hypoglycaemic potential.

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Categories of nutraceuticals and their role in diabetes

Nutraceuticals are non-specific biological therapies used to promote
wellness, prevent malignant processes and control symptoms. These can
be grouped into the following three broad categories.
Nutrients: Substances with established nutritional functions, such as
vitamins, minerals, amino acids and fatty acids.
Herbals: Herbs or botanical products as concentrates and extracts.
Dietary Supplements: Reagents derived from other sources (e.g.,
pyruvate, chondroitin sulphate, steroid hormone precursors)
serving specific functions, such as sports nutrition, weight-loss
supplements and meal replacements. The purpose of this review is
to discuss these issues and provide a methodological framework for
the clinical investigation of nutraceuticals in diabetes mellitus and
metabolic syndrome.
Antioxidants of vitamins
Animal studies have shown that an adequate supply of dietary
antioxidants may prevent or delay diabetes complications including
renal and neural dysfunction by providing protection against oxidative
stress. However, clear evidence in humans is lacking.
Vitamin C
Vitamin C (ascorbic acid) is a chain-breaking antioxidant, scavenging
ROS directly, and preventing the propagation of chain reactions that
would otherwise lead to a reduction in protein glycation. In animals,
vitamin C also reduces diabetes-induced sorbitol accumulation and
lipid peroxides in erythrocytes. Vitamin C (800 mg/day) partially
replenishes vitamin C levels in patients with type 2 DM and low
vitamin C levels but does not improve endothelial dysfunction or
insulin resistance.
Calcium/Vitamin D
One of the first large prospective studies to examine the role of habitual
diet on diabetes risk identified high calcium intake as protective;
women in the top quintile of calcium intake, as contrasted to those in
the bottom quintile, were 30% less likely to develop diabetes over a 6
year follow up, after correction for various potential confounders.
Surprisingly, it appears that no subsequent studies have followed this
lead. No prospective studies have examined the implications of habitual
vitamin D intake (or sunlight exposure) for diabetes risk. Yet there are
theoretical grounds for suspecting that, by suppressing secretion of
parathyroid hormone (PTH), good calcium/ vitamin D status may help
to preserve insulin sensitivity and thus help prevent diabetes mellitus.

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Vitamin E
Vitamin E is an essential fat-soluble vitamin and functions primarily as
an antioxidant. Low levels of vitamin E have been associated with
increased incidence of diabetes and some research suggests people with
diabetes have decreased levels of antioxidants. Additional evidence
indicates that people with diabetes may also have greater anti-oxidant
requirements, due to increased free radical production secondary to
hyperglycaemia. Doses of vitamin E up to 400 IU are generally
believed to be safe. Doses over 800 IU may alter blood clotting
although supplement trials that have monitored Prothrombin times in
subjects have noted no increases.
Carbohydrates
Carbohydrates are the energetic substrate related to the greatest
impact on glycaemia levels. The total amount of carbohydrates is
the main factor responsible for the post-prandial response, but there
are other variables, such as type of carbohydrate, richness in fibre,
the way of cooking, degree of maturity, etc., that can play a role.
Moreover, there are other factors that can also influence post-
prandial glycaemia such as pre-prandial glycaemia, macronutrient
distribution of the whole meal (fats and proteins) and the
hypoglycaemic treatment administered: oral tablets or insulin. Most
scientific societies recommend the individualisation of
carbohydrate contribution, agreeing with the fact that the diet
should provide carbohydrates in the form of fruits, cereals, pasta,
legumes, vegetables and tubers. Although there are no long-term
studies, it seems that eating starches of legumes has a positive
effect on glycaemia, because of the persistent effect on post-
prandial glycaemia, with no sudden increases; it may prevent both
post-prandial hyperglycaemia and late hypoglycaemia.
Fats
Numerous studies indicate high-fat diets can impair glucose tolerance
and promote obesity, dyslipidemia and atherosclerotic heart disease.
Research also shows these same metabolic abnormalities are reversed or
improved by reducing saturated fat intake. Current recommendations on
fat intake for the general population apply equally to people with
diabetes: reduce saturated fats to 10% or less of total energy intake and
cholesterol intake to 300 mg/d or less. Scientific debate continues over
which alternative is preferable to saturated fat polyunsaturated fat,
monounsaturated fat or carbohydrate calories. Research suggests
monounsaturated fat such as canola, olive and peanut oils may have

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beneficial effects on triglycerides and glycemic control in some

individuals with diabetes, but care must be taken to avoid weight gain.
Omega-3 fatty acids, found in fish such as salmon and mackerel may
reduce serum triglycerides without impairing glycemic control.
Fibre
Food’s rich in fibre, such as fruits and vegetables, are still
recommended; special mention is made of whole cereals. Although the
protective effect of fibres against some chronic diseases is well
established the effectiveness of fibres in lipid and glycemic metabolism
remains uncertain. For the general population, an intake of 26 g/day and
38 g/day is recommended, for women and men, respectively. There is
no reason to increase the fibre dose in diabetic patients.
Chromium
Chromium is a trace element that may be deficient in persons with
diabetes. It has been suggested that chromium supplements may
increase insulin sensitivity and improve glucose tolerance in patients
with type 2 diabetes mellitus. A meta-analysis of randomized
controlled trials investigating the effects of chromium
supplementation on glucose and insulin response in healthy
individuals and those with diabetes showed a modest but significant
improvement in glycemic control in the latter, but not in the former.
The American Diabetes Association’s official position is that there is
inconclusive evidence for the benefit of chromium supplementation
in diabetes. Magnesium Prospective epidemiology links magnesium-
rich diets to decreased risk for diabetes, with an inverse correlation
between magnesium intake and fasting insulin levels, suggesting an
improvement in insulin sensitivity. This view is supported by limited
clinical data, as well as by animal studies demonstrating that
magnesium helps preserving adipocyte insulin sensitivity.
The retina is particularly vulnerable to oxidative damage because of
its abundance of polyunsaturated fatty acids, predominantly found in
photoreceptor outer membranes, which are readily oxidized.
Nutritional supplementation for age-related macular degeneration
(AMD) has been investigated in the Age-Related Eye Disease Study
that reported a 25% reduction in the risk of progression to advanced
AMD in people who had later stages of AMD and were
supplemented with a high-dose zinc plus antioxidants formulation.
α- Lipoic Acid
α- Lipoic acid is a naturally occurring antioxidant with potent ROS-
scavenging activity. It has the unusual property of being a ROS

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

scavenger in its oxidized state, quenching several radicals. α- Lipoic

acid and dihydrolipoic acid work in a redox couple (an electron donating
molecule and its oxidized form), and together have other antioxidant
properties including chelation of transition metals and the regeneration
of other antioxidants such as glutathione, Vitamin C and Vitamin E. α-
Lipoic acid has been shown to protect the retina against ischemia-
reperfusion injuries in vivo and in vitro. Ischemic injury to the retina is
considered to be one of the major causes of visual loss and occurs in
diabetic retinopathy. α- Lipoic acid increases insulin sensitivity by
approximately 18–20% in patients with type 2 diabetes mellitus. A
review of the clinical trials of α- Lipoic acid in the treatment of diabetic
neuropathy reported beneficial effects on acute symptoms and disease
progression.
Vanadium
Research indicates that this mineral acts similarly to insulin in
transporting glucose into the cells, and is therefore valuable for both
type 1 and Type 2 diabetes mellitus. Vanadium supplementation also
decreased fasting blood glucose levels, Hemoglobin A1c levels and
cholesterol levels 50. Dosages ranging from 45- 150 mg/day can be
useful for improving fasting glucose levels (how much sugar is in the
blood when one wakes up in the morning). Toxicity studies show these
dosage levels to be safe and well tolerated by most people. Some
individuals experience mild gastrointestinal distress, either during the
first week of use or at higher dosage levels (up to 400 mg/day).
Protein
Current evidence indicates people with diabetes have similar protein
requirements to those of the general population-about 0.86 g/kg per day.
Although protein plays a role in stimulating insulin secretion excessive
intakes should be avoided as it may contribute to the pathogenesis of
diabetic nephropathy. Some evidence suggests eating vegetable protein
rather than animal protein is better for reducing serum cholesterol and
managing nephropathy. There are a number of different types of protein
supplements include liquid protein supplements, protein powders and
liquid protein shots. There are a number of sources for protein
supplements. Some of these sources include: Whey, Casein, Soy, Rice,
and Egg.
Coenzymes Q10
The importance of this nutrient cannot be overstated, primarily because
many of the drugs that are needed for management of diabetes and or
its complications deplete Coenzyme Q10.
Coenzyme Q10 is a promising nutritional intervention for insulin

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DEVELOPMENT AND MANAGEMENT OF NUTRACEUTICALS

resistance, at least among subjects with hypertension. Singh et al

conducted an eight week randomized, double- blind trial comparing the
use of a water soluble form of CoQ10 (60 mg twice daily) to a vitamin
B complex in 59 hypertensive patients. Their results indicated CoQ10 at
this dose lowered glucose and fasting insulin levels, suggesting possible
improved insulin resistance.
L-carnitine
L-carnitine (β-hydroxy -γ - trimethmylaminobutyrate), a natural vitamin
like compound, is an ubiquitous constituent of mammalian plasma and
tissues, mainly distributed among skeletal and cardiac muscles. L-
carnitine is supplied through dietary sources (e.g., meat, dairy products),
and by biosynthesis from lysine and methionine. Supplementation
studies have shown that L-carnitine promotes insulin sensitivity and has
lipid-lowering actions. L-carnitine performs a number of essential
intracellular and metabolic functions, such as fatty acid transport across
the inner mitochondrial membrane into the matrix for β- oxidation,
detoxification of potentially toxic metabolites, regulation of the
mitochondrialacyl-Co A/CoA ratio, and stabilization of cell membranes.
L-carnitine facilitates the elimination of short- and medium-chain fatty
acids accumulating in mitochondria as a result of normal or abnormal
metabolism. L-carnitine also has effects on oxidative metabolism of
glucose in tissues. L-carnitine could improve insulin action in the
fructose- fed rat model of insulin resistance. Skeletal muscle is an
insulin-sensitive tissue, which is also a site of insulin resistance in the
fructose-fed rat and it is vulnerable to oxidative damage. Considering
this, these authors evaluated the role of L-carnitine in mitigating
oxidative stress and lipid accumulation in the insulin sensitive skeletal
muscle in a well- characterized model of insulin resistance. The effects
of L-carnitine in this model suggest that its supplementation may have
some benefits in patients suffering from insulin resistance.

ANTI-DIABETICS CLAIMS OF HERBS

Diabetes mellitus is a worldwide menace and exponentially growing
metabolic disease in India, affecting the lipid and carbohydrate
metabolism and affecting the person physically as well as mentally. The
knowledge on the heterogeneity of this order is advanced, the need for
more appropriate therapy increases.
Traditional herbal medicines are used as a safe alternative for
conventional hypoglycaemic agents, because synthetic drugs in NIDDM
or insulin in IDDM have a limited role to play, and have high risk of

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drug tolerance, thereby causing a raise in dosage or a change of drug. By

virtue of richness in essential phytonutrients, Ayurvedic herbs may help
as “Potentiators” for these drugs and play a supportive role to maintain
the quality of the diabetic life. There is vast potential of selected
medicinal plants from Ayurveda and Indian folk role medicine. Several
works have been attempted by CSIR, ICMR, DBT, and academia on
role of herbal nutraceuticals, nutritional and naturals in metabolic
disorders like diabetes.

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