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Current Pharmaceutical Biotechnology, 2006, 7, 15-23


Nutraceuticals - An Emerging Era in the Treatment and Prevention of

Cardiovascular Diseases
C.S. Ramaa, A.R. Shirode, A.S. Mundada* and V.J. Kadam
Bharati Vidyapeeth College of Pharmacy, Sector-8, C.B.D., Belapur, Navi-Mumbai 400614, India
Abstract: Foods and nutrients play a vital role in normal functioning of the body. They are helpful in maintaining the
health of the individual and in reducing the risk of various diseases. Worldwide acceptance of this fact formed a recognition link between nutrition and health and the concept of nutraceuticals was evolved.
Nutraceuticals are medicinal foods that play a role in maintaining well being, enhancing health, modulating immunity and
thereby preventing as well as treating specific diseases. Thus the field of nutraceuticals can be envisioned as one of the
missing blocks in the health benefit of an individual. More than any other disease, the etiology of cardiovascular disease
reveals many risk factors that are amenable to nutraceutical intervention. The scientific literature shows that several ingredients marketed for use in dietary supplements address each of these. The ability of nutraceuticals to positively influence
cardiovascular risk factors should be recognized as an enormous opportunity in the treatment of a highly prevalent disease.
Nutraceuticals hold promise in clinical therapy as they have the potential to significantly reduce the risk of side effects associated with chemotherapy along with reducing the global health care cost. In this review, an attempt has been made to
summarize some of the recent research findings on garlic, omega-3-fatty acids, soy products, dietary fibres, vitamins, antioxidants, plant sterols, flavonoids, prebiotics and probiotics that have beneficial effects on the heart, in order to update
the practising clinician on the benefit of using nutraceuticals for the management of cardiovascular diseases.

Key Words: Nutraceutical, cardiovascular diseases, coronary heart diseases, prebiotics, omega-3 fatty acids, functional foods.

Sugar alcohols

The term Nutraceutical came into existence in 1989

when Dr. Stephen DeFelice coined the term nutraceutical
from nutrition and pharmaceutical [1]. According to
DeFelice, nutraceutical can be defined as a food or part of a
food that provides medicinal and health benefits, including
the prevention and/or treatment of a disease. Nutraceutical
may range from isolated nutrient diets to genetically engineered designer foods and herbal products.

Polyunsaturated fatty acids

Hippocrates proclaimed some 2500 years ago-Let food

be thy medicine and medicine be thy food [2]. Human nutrition science has moved from the prevention of nutrient
deficiency to emphasis on human health care maintenance
and reduced risk of chronic diseases. Traditionally, food
products have been developed for taste, appearance, value
and convenience of the consumer. The development of products to confirm the health benefit is relatively a new trend,
thus recognizing the growing acceptance of the role of diet in
disease prevention and treatment.


At present eleven categories of functional ingredients or

nutraceuticals exist in Japan as part of FOSHU (Foods for
Specified Health Use) [3].
Dietary fibres
*Address correspondence to this author at the Bharati Vidyapeeth College
of Pharmacy, Sector-8, C.B.D., Belapur, Navi-Mumbai 400614, India;
Tel: +91-09224360591; Fax: +91-22-27571122;
E-mail: atishmundada@rediffmail.com
1389-2010/06 $50.00+.00

Peptides and proteins

Glycosides, isoprenoids and vitamins.
Alcohols and phenols
Cholines (lecithin)
Lactic acid bacteria
Diseases mainly affecting the heart or blood vessels are
primarily termed as cardiovascular diseases (CVDs). Today,
CVDs constitute one of the major causes of mortality and
have become a major health hazard all over the world since
they account for more than 30% of the global deaths every
year, which represent about total current population of the
Australian continent. It is now not restricted to affluent western world alone but the developing countries as well [4].
When we say the mortality rate due to CVDs is high all over
the world, it means that the risk factor associated with
CVDs, such as obesity, unhealthy diet, lack of physical exercise, present day work style and quick fix foods have not
been addressed to appropriately by all concerned. Few people know that a little readjustment of life style and healthy
2006 Bentham Science Publishers Ltd.


Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1

living habits can contain and control the incidence of CVDs

globally. Four properties of the cardiovascular system are
primarily evaluated to provide information to help manage
this dreaded affliction: movement of electrical signals
through the heart, heart pump function, blood flow through
the heart and anatomy [5].
Nutraceuticals have been found to be beneficial in the
prevention and risk management of CVDs and may be
broadly classified as those used in prevention or treatment of
Congestive heart failure, arrhythmias, hypertension, angina
and hyperlipidemias.
In the following section various nutraceuticals are discussed which are used and proved best in the prevention and
treatment of CVDs.
Since long, high levels of blood cholesterol and plasma
triglycerides have been associated with artherosclerosis and
ischemic heart disease. Garlic exerts its antihyperlipidemic
effect by the increased excretion of cholesterol end products
in the faeces and by the reduced endogenous synthesis of
cholesterol. It gives a more favorable HDL: LDL ratio [6, 7].
The cholesterol lowering effects of garlic have been attributed not only to its organosulfur constituents but also to a
variety of steroidal saponins present in garlic and aged garlic
extract [8]. Strong effects on cholesterol level can be
achieved if the active principles allicin and alliin can be
protected from gastric acids.
Thirteen placebo controlled trials involving 781 patients
have evaluated the effect of garlic supplementation on serum
cholesterol. A dose of 600-900mg per day of standardized
extract was found to diminish serum cholesterol by
0.41mmol/l [9]. Apart from antihyperlipidemic property,
Garlic also has some inherent antihypertensive effect [10].
These are polyunsaturated fatty acids (PUFAs) derived
mainly from marine sources. Following an early 1970s observational investigation that Omega 3s may reduce the incidence of deaths related to myocardial infarction in Greenland Eskimos, several trials have been done to support this
finding. Marine omega-3 eicosapentaenoic acid (EPA) and
docosahaexanoic acid (DHA) have been shown to play a
crucial role in prevention of CVDs. The diet and reinfarction
trial (DART), a randomized trial involving 2033 men post
myocardial infarction demonstrated that fish oil supplement
intake reduced mortality by 29% over a period of 2 years
One of the milestone studies was the GISSI Prevenzione
trials in Italy, an open label trial involving 11,324 patients
followed up for 3.5 years. It was a 2x2 factorial design and
the subjects were designed to receive either fish oil 900mg
capsule EPA: DHA of 2:1 or placebo and vitamin E randomly. Fish oil consumption was associated with a significant decrease in sudden deaths by 45% and cardiovascular
deaths by 30% and 20% reduction in total mortality [12].
Additional evidence in this direction was obtained from
the Kuopio heart study conducted in Finland. The study was

Ramaa et al.

a prospective one involving 1871 men between 42 and 60

years of age who on baseline examination showed no signs
of coronary heart disease (CHD) clinically. During follow-up
194 men sustained a fatal or non-fatal CHD event. Men in
the highest quintile of omega-3-fatty acid consumption had a
44% reduced risk of CHD (p=0.014) as compared to those in
the lowest quintile. In men in the highest quintile, the risk of
CHD was reduced by 67% when omega-3-fatty acid supplementation was along with a low content of mercury
(p=0.016) [13].
Marine lipid supplementation decreases the progression
of CHD on repeat angiography and improves coronary artery
bypass vein graft potency [14]. The source of omega 3s is
important especially when comparing plant sources to marine sources. Whether the body can convert the medium
chain omega-3 fatty acid alpha linolenic acid from plant
sources into EPA and DHA is still a debatable issue. Recent
clinical trials have found that omega-3 fatty acids reduce the
risk of cardiac arrhythmias as well and modestly reduce hypertension and artherosclerosis related plaque formation [15,
Omega-3 fatty acids appear to offer protection against
arrhythmias by enhancing the electrical stability of the heart
cells and prolonging its relative refractory period [3, 17].
Omega-3-fatty acids have been recommended as a promising
secondary prevention measure against CVDs, in fact studies
have indicated a similar or superior benefit to statins in secondary prevention [18, 19].
The mechanisms and cardiovascular effects of omega-3
fatty acids have been reviewed by Mueller and Talbert [20].
The cardiovascular benefits of these fatty acids have been
suggested to be due to competition with omega-6 fatty acids
for prostaglandin and leukotriene pathways and also due to
increase in cell membrane fluidity as a result of a high degree of unsaturation.
Carroll and Roth reviewed the beneficial effects of
omega-3 fatty acids on the cardiovascular system [21].
Based on epidemiologic and clinical trials they documented
that omega-3-fatty acids reduce the risk of cardiovascular
deaths by 29 to 52%, risk of sudden cardiac death by 45 to
81%. They further reported that although omega-3-fatty acids are fairly well tolerated, potential adverse effects include
bloating and gastro-intestinal distress, fishy taste, hyperglycemia, increased risk of bleeding and a slight increase in
LDL cholesterol.
The American Heart Association (AHA) recommends 24g of EPA and DHA per day as supplement for people who
have elevated triglycerides. In addition, AHA recommends
even healthy individuals to consume omega-3-fatty acids
from fish and plant sources to protect their hearts [22].
Soy contains several different nutrients; however the two
that got the most attention are soy proteins and soy isoflavones. Most research has focused on soy proteins. U.S.FDA
approved a health claim in 1999 stating 25g of soy proteins
a day, as part of a diet low in saturated food and cholesterol
may reduce the risk of coronary heart disease [23]. Many of
the benefits of soy have been attributed to soy isoflavones

Nutraceuticals - An Emerging Era in the Treatment and Prevention

however the role of isoflavones of soy in reducing cholesterol is still unclear due to conflicting reports. The relatively
short duration and small sample size of many of the human
studies in this field likely contribute to the inconsistent results. Soy and its associated isoflavones reduce LDL oxidation and improve vascular reactivity [24].
Based on the review of more than 50 recent trials, Hermansen et.al. reported that consumption of new soy products
containing high fixed levels of isoflavones, cotyledon soy
fibre and soy phospholipids (Abaco and Abalon) significantly reduced the LDL: HDL. On an average Abaco and
Abalon reduced the LDL: HDL ratio by 20%, LDL cholesterol by 15%, total cholesterol by 10% and triglycerides by
6% and increased HDL cholesterol by 5% [25].
Sanders et.al. conducted randomized cross over trials in
22 young, healthy normolipidemic subjects (5 men and 17
women) who consumed diets providing 56 or 2 mg isoflavones per day for 17 days each with a 25 day wash out period between treatment. They reported that as compared to
soy protein from which most of the phytoestrogens (high
isoflavone content) have been extracted, soy protein with
intact phytoestrogens increases HDL-cholesterol and Apolipoprotein A-1 concentration, but does not influence LDLcholesterol, TGF-beta-1 concentrations and hemostatic risk
factors for coronary heart disease in normolipidemic healthy
subjects [26]. In contrast, in another study in which 41 hyperlipidemic men and postmenopausal women participated,
the conclusion was that substitution of soy foods for animal
products, regardless of isoflavone concentration, reduces the
coronary artery disease risk, because of both modest reduction in blood lipids and reduction in oxidized LDL, homocysteine and blood pressure [27].
Typically soy foods are divided into two categories: nonfermented and fermented soy products. Traditional nonfermented soy foods include fresh green soybeans, whole dry
soybeans, soy nuts, soy sprouts, whole-fat soy flour, soymilk
and soymilk products, tofu, okara and yuba. Traditional fermented soy foods include tempeh, miso, soy sauces, natto
and fermented tofu and soymilk products [28]. In Asia, the
traditional fermented soy foods are considered to have more
health promoting benefits when consumed in moderate
amounts than the super-processed soy products that are consumed in the West [29, 30]. It has been suggested that the
fermentation process increases availability of isoflavones in
soy [28, 31].
Fibres are the endogenous components of plant materials
in the diet, which are resistant to digestion by enzymes produced by humans. Fibres can be broadly classified into soluble and insoluble fibres as per their solubility in the blood
stream. Since all foods contain a mixture of polysaccharides,
only isolated polysaccharides can be simply classified as
soluble or insoluble fibre sources [32]. Fibre is important for
gastrointestinal health as well as cholesterol-lowering benefits [33]. Insoluble fibre reduces rate of colon cancer and
diverticulitis, an inflammatory condition of the colon, while
soluble fibre significantly lowers blood cholesterol, thus reducing the risk of CHD [34-39].

Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1


Wheat, rye, rice, and most other grains are primarily

composed of insoluble fibre. Barley offers both but is mainly
insoluble fibre. Soluble fibre can be mainly derived from oat
bran and fruit pectin. Other sources include psyllium husks
and flax seeds. Legumes, beans, peas, certain fruits and
vegetables are excellent sources of both soluble and insoluble fibres. The AHA dietary guidelines for Americans emphasize the importance of consuming a variety of fibre
sources to obtain the different types of fibres found in foods.
Within the past decade food composition databases have
reflected technological advances by listing specific values
for total, soluble, and insoluble dietary fibre [33].
Oats have a greater proportion of soluble fibre than any
other grain, with almost 7 g of total fibre and 2 g of soluble
fibre in a one-half cup serving. Intake of dietary fibres, particularly soluble fibres have been proven to reduce the blood
cholesterol levels, thus helping to reduce the risk of CHD.
Recent findings provides evidence that viscous polysaccharides act in the gastrointestinal tract to reduce blood cholesterol by decreasing absorption of cholesterol or fatty acids
and decreasing absorption of biliary cholesterol or bile acids
[37]. Fibres may also cause altered serum concentration of
hormones or short-chain fatty acids that affect lipid metabolism. -Glucan, the water-soluble fibre prevalent in oats and
barley, has been shown in animal models to be the active
agent causing the altered cholesterol metabolism [38, 39].
Soy protein products are also an excellent source of dietary fibre [25]. Since dietary fibre seems to play a role in
controlling blood cholesterol, and may have an effect in preventing colon cancer and improving glucose tolerance, studies with diets containing soy flour, soy concentrate or soy
fibre merit special attention. Diets low in dietary fibre have
been correlated with increased incidence of colon cancer,
coronary heart disease, diabetes, diverticulitis and various
other maladies of the lower gastrointestinal tract in man. A
growing number of metabolic research studies have reported
total cholesterol reductions of 10% to 15% with diets enriched with fibre from oats, beans, or psyllium, but these
diets were also reduced in fat [39].
The physicochemical properties of soluble fibres result in
important alterations in volume, bulk and viscosity in the
lumen of the intestine [40]. Dietary fibres of flaxseed contain
6% mucilage, which is of benefit in reducing coronary heart
disease [41]. Oat also exerts a beneficial action on heart
muscles. Consumption of 50g of rolled oats per day showed
a marked decrease in the serum cholesterol content of human
males [42]. In a pooled analysis of data from 10 prospective
cohort studies among 91058 men and 245186 women followed up over 6 to 10 years, each 10g per day increment of
total dietary fibre was associated with 14% decrease in risk
of all coronary events and 27% decrease in risk of coronary
death. Results were similar for both genders [43]. Hence
diets low in saturated fats and cholesterol and rich in fruits,
vegetables and grain products containing dietary fibres, particularly soluble fibres, may be beneficial in reducing the
risk of heart disease.
Diets high in complex carbohydrates and fibre are associated with reduced mortality rates from CHD and other
chronic diseases. Fibres found in oats, barley, and pectin-rich
fruits and vegetables provides adjunctive lipid-lowering


Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1

Ramaa et al.

benefits beyond those achieved by reductions in total and

saturated fat alone. The AHA recommends a total dietary
fibre intake of 25g to 30g per day from foods, not supplements, to ensure nutrient adequacy and maximize the cholesterol-lowering impact of a fat-modified diet. Current dietary fibre intakes among adults in the United States average
about 15g, or half the recommended amount [44, 45].
Mechanisms by which fibres may protect against CHD
include lowering blood cholesterol (soluble fibres), attenuating blood triglyceride levels (mostly soluble fibres), decreasing hypertension (all fibres), and normalizing postprandial blood glucose levels (all fibres). An important consideration in making diet recommendations to protect against
CHD is that the total amount of fibre from fibre-containing
foods is important, and individuals should not just be counseled to focus on soluble fibres [46].
One of the major risk factors associated with CVD is
hypertension. Angiotensin converting enzyme (ACE) inhibitors have constituted a main line of therapy in the control
of hypertension. However, their use has been associated with
several side effects including hypotension, increased levels
of potassium, reduced renal function, cough, angioedema,
skin rashes and fetal abnormalities [47]. Proteins such as
casein and whey from milk form a rich source of ACE inhibitory peptides [48]. Several studies in spontaneously hypotensive rats showed that these peptides derived from milk
protein exert an antihypertensive effect. This has been supported by a limited number of human studies, which showed
statistically significant hypotensive effects. It has been hypothesized that excessive milk consumption may have an
adverse effect on circulation due to its high calcium content,
which promotes calcification and rigidification of large elastic arteries leading to myocardial ischemia [49].
Proteins on complete hydrolysis yield component amino
acids. Vegetable proteins are rich sources of arginine. Larginine, a non-essential amino acid being a nitric oxide
synthase precursor augments the production of nitric oxide,
which in turn acts as a vasodilator thus helping to improve
dysfunctional coronary sympathetic responses. In medically
treated hypertensive patients with microvascular angina, oral
L-arginine may be therapeutically useful [50].

Table 1.

Antioxidant vitamins present in some fixed oils, fruits,
vegetables and fishes are those compounds, which either
prevent the formation of oxygen free radicals or entrap them.
Antioxidants are the magic bullets for a wide range of diseases including cancer and cardiovascular disease. Their
primary function is to counter the damaging effect of free
radicals in our body, thereby reducing LDL-cholesterol oxidation [51]. Although niacin has been first demonstrated to
have an antihyperlipidemic effect, the emergence of HMGCoA inhibitors has reduced its use.
Clinical use of antioxidant vitamin supplementation may
help to prevent CHD. Epidemiologic studies found lower
CHD morbidity and mortality in persons who consume
larger quantities of antioxidants in foods or supplements.
Clinical trials indicate that supplementation with certain nutrients is beneficial in reducing the incidence of CHD events.
Supplementation with antioxidant vitamins E and C has
benefits in CHD prevention; however, supplementation with
-carotene may have deleterious effects and is not recommended [51]. Adams et.al. suggested that patients with CHD
would probably benefit from taking vitamin E in a dosage of
400 IU per day and vitamin C in a dosage of 500 to 1,000
mg per day. Clinicians may also want to consider vitamin
supplementation for CHD prevention in high-risk patients
In the Heart Outcomes Prevention Evaluation Study
(HOPE) in which 9279 patients belonging to the high-risk
category for CHD events participated. In a 2x2 factorial design, patients were randomly assigned to receive ramipril or
placebo and vitamin E (400 IU per day) or placebo. They
were followed up for 3.5yrs. Vitamin E supplementation was
without any benefit [53, 54].
Many epidemiologic studies have linked diets high in
antioxidants with reduced CHD risk (Tables 1 [54-57] and 2
[58-62]). Randomized, controlled trials of antioxidant vitamin supplementation are summarized in Table 3 [63-69].
Supplementary vitamin E in a dosage of greater than 100 IU
per day was associated with reduced lesion progression.
Clinical trials strongly supports that vitamin E in dosages
greater than 100 IU per day reduces CHD events. CHD relative risk reductions of 31 to 65 percent were found with vitamin E supplementation [52] Patients receiving warfarin

Observational Study on the Relationship between Antioxidant Vitamins and Coronary Heart Disease (CHD)





16 European regions

Inverse association between plasma vitamin E level and CHD mortality;

inverse association between plasma vitamin C and CHD mortality
in a subset of 12 normocholesterolemic populations

Verlangieri, et al.

United States

Inverse association between fruit and vegetable consumption and CHD mortality

Riemersma, et al.

110 angina patients and 394 control subjects

Lower plasma vitamin E levels in angina patients than in control subjects

Luoma, et al.

Northern Finland

Inverse association of plasma vitamin E level and CHD mortality

WHO = World Health Organization; MONICA = Multinational Monitoring of Trends and Determinants in Cardiovascular Disease.

Nutraceuticals - An Emerging Era in the Treatment and Prevention

Table 2.

Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1


Prospective Cohort Studies on the Relationship between Antioxidant Vitamins and Coronary Heart Disease

Vitamin E

Vitamin C





Nurses Health Study (females)

Health Professionals Study (males)

+(Smokers only)



Scottish Heart Health Study

NHANES = National Health and Nutrition Examination Survey I; EPESE = Established Populations for Epidemiologic Studies of the Elderly; + = Significant inverse relationship
benefit observed between vitamin and coronary heart disease; 0 = no significant relationship observed; X = vitamin not studied.

Table 3.

Randomized Controlled Trials on the Relationship between Antioxidants and Coronary Heart Disease (CHD)





Primary prevention


50 mg per day

Secondary prevention

ATBC subset

50 mg per day

+ (Alone)
- (with -carotene)


400 or 800 IU per day


>100 IU per day

+ (Dose dependent)

Primary prevention

Chinese Cancer Prevention Trial

125 mg per day

Secondary prevention


Primary prevention


20 mg per day

Chinese Cancer Prevention Trial

15 mg per day

+ (Combined with vitamin E

Prevention Trial and selenium)

Vitamin E

Vitamin C


Secondary prevention


Physicians' Health Study

ATBC subset

20 mg per day

- (Alone and combined with vitamin E)

ATBC = Alpha-Tocopherol Beta-Carotene Cancer Prevention Study; CHAOS = Cambridge Heart Antioxidant Study; CLAS = Cholesterol Lowering Atherosclerosis Study; CARET
= Beta-Carotene and Retinol Efficacy Trial; + = Significant positive effect of vitamin supplementation on CHD; - = Significant negative effect of vitamin supplementation on CHD;
0 = no effect of vitamin supplementation on CHD.
*--A portion of this study (on intake of vitamins C and E) was not randomized.

(Coumadin) therapy should limit vitamin E intake to 200 IU

per day and should avoid vitamin E if they are at high risk
for bleeding. Cohort studies suggest that patients with conditions in which LDL oxidation is common (i.e., diabetes,
smoking, hypertension) may benefit from vitamin E supplementation in a dosage of 200 to 400 IU per day. Vitamin E
supplementation was of benefit, according to the GISSIPrevenzione trial [70]. This trial proved that vitamin E consumption was associated with 23 to 35% reduction in death
or cardiovascular events.
A meta analysis of the effect of high vs. low vitamin E
intake on cardiovascular mortality has demonstrated no
benefit in intervention studies as against in observational
studies [74]. Asplund has systematically reviewed the role of
antioxidant vitamins in the prevention of cardiovascular dis-

ease and reported that supplement use is a component in a

cluster of healthy behaviour [72].
The National Health and Nutrition Examination Survey-I
cohort study found an inverse relationship between the highest vitamin C intake (diet and supplements) and CHD risk
over 10 years in 11,349 American men and women between
25 to 74 years of age [73]. Patients were randomized to receive different combinations of 10 nutritional supplements
for five years. The patients who received vitamin C in a dosage of 125 mg per day and molybdenum in a dosage of 30
g per day demonstrated no significant reduction in total or
cerebrovascular mortality.
Many studies have demonstrated the ability of vitamin C
to improve arterial vasoreactivity. A single dose (2 g) of vitamin C has been found to improve vasoreactivity in chronic


Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1

smokers [74], patients with hypercholesterolemia and patients with CHD [75]. These findings support the antioxidant
and endothelial effects of vitamin C.
Lycopene is a carotenoid, which is the main active constituent in tomatoes, and has been a recent focus in cardiovascular health research. Findings suggest that dietary lycopenes or other phytochemicals consumed as oil based tomato
products confer cardiovascular benefits [22]. Natural tomato
lycopene rather than synthetic lycopene has been found to
confer heart health benefits.
Antioxidant vitamins have also been proved beneficial in
countering endothelial dysfunction, which is an early step in
the development of artherosclerosis [76]. Folate lowers elevated homocysteine level, but evidence suggesting routine
use as supplement does not exist. The role of beta-carotene in
CHD is also dubious and may have deleterious effects [51].
Pantothenic acid lowered LDL-cholesterol by 13.5% and
increased HDL-cholesterol by 10% in a study of 11 patients
Other antioxidants that may provide protection against
CHD include selenium, bioflavonoids and ubiquinone.
Selenium levels are inversely associated with CHD mortality
[78], conflicting results were reported in other studies [79].
Ubiquinone, a reduced form of coenzyme Q10, decreases
LDL oxidation, but no event reduction data are available.
Ubiquinone may reduce symptoms and improve ejection
fractions in patients with heart failure [80-82].
Plant sterols also known as phytosterols are found naturally in a range of plant sources such as vegetable oils, nuts,
grains, seeds, wood pulp and leaves. Typical diets commonly
include sitosterol, campesterol and stigmasterol along with
smaller amounts of plant stanols (saturated plant sterols) like
sitostanol. Being structurally similar to cholesterol, they
compete with ingested cholesterol for absorption through the
small intestine. This reduction in absorption of cholesterol
increases hepatic uptake of LDL and reduces blood LDL
levels, although there are compensatory mechanisms that
increase the rate of endogenous cholesterol synthesis which
limit the magnitude of the effect [83].
Plant sterols have been shown in studies to reduce LDL
cholesterol by 8-15%. Plant sterols are derived from natural
grains including soy, corn and sunflower. Studies have demonstrated the efficacy of plant sterols in reducing the risk of
CHD [84]. However long term use might lead to a decrease
in plasma carotenes, vitamin-E and lycopene. AHA has recommended restricted use to adults only requiring treatment
for hypercholesterolemia or needing secondary prevention of
CHD [85]. Various studies suggested that the consumption
of about 2-3gm per day of plant sterols/stanols reduce LDLcholesterol levels between 9%-20% although there is considerable variation amongst individuals [86]. Little effect on
HDL-Cholesterol or triglyceride levels has been reported.
Plant stanol ester margarines have also been shown to be
effective adjunct to hypercholesterolaemia treatment using
statins and fibrates [86, 87].
Foods that may qualify for the health claim based on
plant sterol ester content include spreads and salad dressings.

Ramaa et al.

Among the foods that may qualify for claims based on plant
stanol ester content are spreads, salad dressings, snack bars,
and dietary supplements in softgel form. U.S.FDA authorized new coronary heart disease health claim that 1.3gm per
day of plant sterol esters or 3.4gm per day of plant stanol
esters in the diet are needed to show a significant cholesterol
lowering effect. In order to qualify for this health claim, a
food must contain at least 0.65gm of plant sterol esters per
serving or at least 1.7gm of plant stanol esters per serving.
The claim must specify that the daily dietary intake of plant
sterol esters or plant stanol esters should be consumed in two
servings eaten at different times of the day with other foods
[88]. This interim final rule was based on U.S.FDA's conclusion that plant sterol esters and plant stanol esters reduces the
risk of CHD by lowering blood cholesterol levels.
The flavonoids, which occur both in free state and as
glycosides, are the largest group of naturally occurring phenols. Polyphenolic compounds, which suggested playing a
dominant role in the prevention of heart disease, include the
isoflavones, flavonoid glycosides, catechins, and anthocyanins [89]. These effects have been attributed to the influence of flavonoids on arachidonic acid metabolism [3, 89].
Flavonoids are antioxidants found in tea (green and
black), wine, fruits and vegetables. These antioxidants
reduces platelet activation, but studies do not yet support an
associated reduction in CHD [90, 91]. An epidemiologic
study found inverse correlation between dietary flavonoid
intake and CHD [91]. Flavonols and flavones are subgroups
of flavonoids. As they have antioxidant properties, intake of
these dietary compounds is associated with a lower risk of
fatal and nonfatal CHD [92].
In a study conducted on 15 patients with coronary artery
disease, consumption of red wine or purple grape juice offered increased protection against LDL-Cholesterol oxidation and also improved endothelial function. Hence it was
suggested that moderate amounts of red wine and purple
grape juice be included among 5-7 daily servings of fruits
and vegetables per day as recommended by AHA to reduce
the risk of cardiovascular disease [93]. A reduced incidence
of CHD and other vascular diseases is well related to a high
dietary intake of flavonoids from fresh fruit and vegetables
[94, 95].
Anderson et al. suggested that isoflavones associated
with soy protein might be responsible for their cardioprotective effect. In support of this suggestion, the results of a dietary trial in monkeys fed semipurified atherogenic diets
showed that the presence of large amounts of isoflavones
was associated with a favourable lipid profile, including a
lower concentration of lipoprotein A [96, 97]. The beneficial
effects observed in the epidemiologic studies, confirmed that
flavonoids represent an important part of a daily "health" diet
A prebiotic is defined as a nondigestible food ingredient
that beneficially affects the host by selectively stimulating
the growth and/or activity of one or a limited number of

Nutraceuticals - An Emerging Era in the Treatment and Prevention

bacteria in the colon [99]. Modification by prebiotics of the

composition of the colonic microflora leads to the predominance of a few of the potentially health-promoting bacteria,
especially, but not exclusively, lactobacilli and bifidobacteria. They are the microbial food supplements, which improve
the hosts intestinal microbial tolerance and thereby have the
potential to prevent major diseases like cancer and lower
serum cholesterol [100]. Non-digestible oligasaccharides
(prebiotics) stimulates the growth of intestinal microflora
The only prebiotics for which sufficient data have been
generated to allow an evaluation of their possible classification, as functional food ingredients are the inulin-type fructans, which include native inulin, enzymatically hydrolyzed
inulin or oligofructose, and synthetic fructooligosaccharides
[102, 103]. At this point, it is worth mentioning that as consumers are showing an interest in heart healthy products,
there is a boom of such nutraceuticals in the market. Included among these can be those traditional foods for which
recent research findings have countered old dogma about
potential cardiovascular health risk.
An excellent example is egg, which was not traditionally
considered a functional food due to notions that it adversely
affected serum cholesterol levels. It is now found that consumption of upto a couple of eggs a day does not adversely
affect blood cholesterol levels. In fact, eggs are an excellent
source of many essential dietary components such as protein,
choline, lutein/zeaxanthin that may improve general health
Probiotics are live microorganisms administered in adequate amounts, which confer a beneficial health effect on the
host. A probiotic is defined classically as a viable microbial
dietary supplement that beneficially affects the host through
its effects in the intestinal tract. This definition, however,
was initially intended for use with animal feed products. For
human nutrition, the following definition has been proposed:
"a live microbial food ingredient that is beneficial to health"
[105]. Probiotic bacteria favorably alter the intestinal microflora balance, inhibit the growth of harmful bacteria, promote good digestion, boost immune function and increase
resistance to infection [106, 107].
Probiotics are widely used to prepare fermented dairy
products such as yogurt or freeze-dried cultures. In the future, they may also be found in fermented vegetables and
meats [108]. Probiotics (live organisms) in the form of fermented milk products have been shown to exert cholesterol
lowering properties, whereas non-digestible fermentable
carbohydrate prebiotics have been shown to reduce triacylglycerol levels in animal studies. However, in human studies
using both prebiotics and probiotics, there have been inconsistent findings with respect to changes in lipid levels [104].
Friendly bacteria live inside intestine and help to digest
food, break down proteins, help process bile, and lower
cholesterol in the arterial walls. Medical scientists are not
certain of the exact mechanisms surrounding how friendly
bacteria function to reduce fat levels in the body. Numerous
studies, however, have demonstrated that Lactobacillus aci-

Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1


dophilus, Bifidobacteria bifidum, and Lactobacillus bulgaricus bacteria lower cholesterol in a significant fashion when
its level is too high [109-113].
The hypocholesterolemic effects of probiotics are the
subjects of controversy. Studies published in the 1970s and
1980s consistently reported 517% reductions in serum cholesterol concentrations after 2 to 4 weeks of daily consumption of fermented milk products, but these data have been
challenged by the results of more recent studies, almost all of
which did not report any significant effect. As discussed recently by Jackson et al., the major limitations of these earlier
studies were as follows: 1) the excessive volumes (0.58.4 L)
of yogurt consumed daily in most of the positive studies, 2)
failure to assess or control for the background diet and exercise patterns of the subjects studied, 3) failure to randomize
groups for confounding factors, 4) lack of run-in periods
during which the volunteers adapted to the diet, 5) lack of
multiple baseline measurements, and 6) changes in control
groups. Jackson et al. concluded that experimental evidence
does not support a hypocholesterolemic effect for probiotics
when consumed in easily achievable quantities [112].
If cholesterol problem is linked to a high fat diet, putting
beneficial bacteria back into the intestine as supplements
offers a natural way to help balance out lipid and fat levels.
A research report from Denmark published in the European
Journal of Clinical Nutrition noted that lactobacillus bacteria
significantly lowered blood pressure in men and women 18
to 55 years of age after eight weeks of supplementation
[111]. Those in the control group who did not receive the
selected strains of lactobacillus bacteria did not experience a
drop in their high blood pressure. Thus, there is significant
evidence that specific kinds of lactobacillus bacteria and
bifidobacteria can lower the three major risk factors for CHD
and stroke: excessive cholesterol, high blood pressure, and
high triglyceride levels. But one has to be careful with the
strain selection of the beneficial bacteria supplement used to
get the best results. Not all strains of L. acidophilus, B. bifidum, and L. bulgaricus bacteria available on the market
work to lower cholesterol [113-115].
CVDs are not the consequence of a single isolated risk
factor but the result of a merging of several complex processes that commence early in life. These include behavioral,
environmental, and socio-economic as well as genetic risk
factors. The focus of the pharmaceutical industry should now
be towards maintenance of optimal heart health rather than
treatment of people with cardiovascular disease. There are
multiple ways to address heart health, either use supplements
that directly affect heart health or use those that help to reduce weight, improve general activity and achieve long term
heart goals.
Some functional foods have intrinsic heart health promoting constituents; others have such constituents added,
while third category includes those in which ingredients
harming heart health are exchanged. These foods include
garlic, polyunsaturated fatty acids from plant and marine
sources; soy products; dietary fibres in oats; psyllium husk
and flaxseed; peptides from milk proteins; antioxidant vitamin containing foods; certain grapes and many others.


Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1

Ramaa et al.

Regular consumption may serve to reduce the risk of cardiovascular disease by several potential mechanisms such as
enhancing electrical stability of heart cells, reducing LDL
oxidation, scavenging free radicals, lowering blood lipids,
reducing blood pressure, inhibiting platelet aggregation and
decreasing plaque formation. As physicians increase their
awareness regarding natural products to promote cardiovascular health, they may include them in their treatment alternatives.




Authors would like to acknowledge Mr. Kasarle, Head, R

& D (Nutraceuticals), Alkem Labs. Ltd., Taloja, INDIA for
his valuable support for the preparation of this article.






Cardiovascular diseases



Coronary heart disease


American Heart Association


Eicosapentaenoic acid


Docosahaexanoic acid


High density lipoproteins



Low density lipoproteins



Angiotensin converting enzyme



Hydroxy methyl Glutaryl Coenzyme A


Kalra, E.K. (2003) AAPS Pharm. Sci., 5(2), 1-4.

William, R.E. Handbook of nutraceuticals and functional foods. Ist
edition; Boca Raton, FL; CRC press. pp. 2-11.
Bawa, A.S., Khanum, F. (2003) Indian Food Industry, 22(6), 4450.
Majid, Ezzati. (2005) PLoS Med., 2(5), e148
American Heart Association medical/scientific statement. Classification of functional capacity and objective assessment of patients
with diseases of the heart. (1994) Circulation, 90, 644-645
The wealth of India. Raw materials, Vol.IA, CSIR India, New
Delhi, (1985) pp. 185.
William Charles Evans, Pharmacological activities. Chapter 17. In,
Trease and Evans; Pharmacognosy. Eds. W.C.Evans. 14th edition.
W.B.Saunders Company limited. pp. 167.
Matsuura, H. (2001) J. Nutr., 131(3S), 1000S-1005S.
Stevenson, C., Pittler, M.H., Ernst, E. (2000) Ann. Intern Med.,
133, 420-429.
Silagy, C., Neil, A. (1999) J. Hypertens., 12, 463-468
Burr, M.L., Fehily, A.M., Gilber, J.F. (1989) Lancet, 2, 757-761.
Ressanen, T., Voulelainen, S., Nyyssonen, K. (2000) Circulation,
102, 2677-2679.
Von Schacky, C., Angerer, P., Kothny, W. (1999) Ann. Intern.
Med., 130, 554-562.
Eritsland, J., Arnesen, H., Gronseth, K. (1996) Am. J. Cardiol ., 77,
Sigal Isaacson, C.I., Wylie-Rosett, J. (1999) Heart Dis., 1(3), 149154.
Simopoulos, A.P. (1997) Can. J. Physiol. Pharmacol., 75(3), 234249.
Lee, K.W., Lip, G.Y. (2003) QJM, 96(7), 465-480.
Bhatnagar, D., Durrington, P.N. (2003) Int. J. Clin. Pract., 57(4),
Richter, W.O. (2003) Eur. J. Med. Res., 8(8), 332-336.
Mueller, B.A., Talbert, R.L. (1998) Clin. Pharm., 7(11), 795-807.
Carroll, D.N., Roth, M.T. (2002) Ann. Pharmacother., 36(12),




Linda, Milo Ohr. Nutraceuticals and Functional foods. (2003)

Food Technology, 57(10), 71-77.
FDA approves new health claim for soy protein and coronary heart
disease. FDA talk paper, Oct 20 (1999) T99-48.
Hasler, C.M. (2002) J. Cardiovasc. Nurs., 16(4), 50-63
Hermansen, K., Dinesen, B., Hoie, L.H., Morgenstern, E., Greenwald, J. (2003) Adv. Ther., 20(1), 50-78.
Sanders, T.A., Dean, T.S., Grainger, D., Miller, G.J., Wiseman, H.
(2002) Am. J. Clin. Nutr., 76(2), 373-377.
Jenkins, D.J., Kendall, C.W., Jackson, C.J., Connelly, P.W., Parker,
T., Faulkner, D., Vidgen, E., Cunnane, S.C., Leiter, L.A., Josse,
R.G. (2002) Am. J. Clin. Nutr., 76(2), 365-372.
Golbitz, P. (1995) J. Nutr., 125 (Suppl. 3), 570S-572S.
Messina, M., Barnes, S. (1991) J. Nat. Cancer Institute, 83(8), 541546.
Messina, M.J., Persky, V., Setchell, K.D. (1994) Nutr. Cancer, 21,
Hutchins, A.M., Slavin, J.L., Lampe, J.W. (1995) J. Am. Diet Assoc., 95(5), 545-551
National Academy of Sciences. Diet and Health. Washington, DC,
National Academy Press; 1989.
The Nutrition Committee, American Heart Association. Dietary
guidelines for healthy American adults. (1996) Circulation, 94,
Bazzano, L.A., He, J., Ogden, L.G., Loria, C.M., Whelton, P.K.
(2003) Arch. Intern. Med., 163(16), 1897-1904.
Pereira, M.A., OReilly, E., Augustsson, K., Fraser, G.E., Goldbourt, U., Heltmann, B.L., Hallmans, G., Knekt, P., Liu, S., Pietinen, P., Spiegelman, D., Stevens, J., Virtamo, J., Willett, W.C.,
Ascherio, A. (2004) Arch. Intern. Med., 164(4), 370-376.
Mia, M.A., Siddiqui, M.N., Haque, M.S., Islam, M.N., Rukkunzaman, M., Deb, K. (2002) Mymensingh Med. J., 11(2), 133-135.
Bagger, M., Anderssen, O., Nielsen, J.B., Ryttig, K.R. (1996) Br. J.
Nutr., 75(3), 483-493.
Anderson, J.W., Smith, B.M., Gustafson, N.J. (1994)
Am.J.Clin.Nutr. 59 (suppl), 1242S-1247S.
Shinnick F, Mathews R, Ink S. (1991) Cereal Foods World, 36,
Fernandez, M.L. (2001) Curr. Opin. Lipidol., 12(1), 35-40.
Rangari, V.D. Pharmacognosy and Phytochemistry-part II, 1st
edition, (2003) Career publications, Nasik. Pp, 67-97.
Wealth of India. Raw materials Vol.I-A. CSIR India, New Delhi,
(1985) Pp, 495.
Fitzgerald, R.J., Murray, B.A., Walsh, D.J. (2004) J. Nutr., 134(4),
Shinnick, F., Mathews, R., Ink, S. (1991) Cereal Foods World, 36,
Hunninghake, D.B., Miller, V.T., LaRosa, J.C., Kinosian, B.,
Jacobson, T., Brown, V., Howard, W.J., Edelman, D.A., O'Connor,
R.R. (1994) Am. J. Med., 97(6), 504-508.
Lupton, J.R., Turner ND. (2003) Curr. Atheroscler. Rep., 5(6),
Jackson, E.K. Renin and angiotensin. In, Goodman and Gilmans,
The pharmacological basis of therapeutics. 10th edition, (2001)
McGraw Hill medical publishing division, New Delhi. pp. 828-829.
Seely, S. (2000) Med. Hypotheses, 54(5), 701-703.
Gellman, J., Hare, J.M., Lowenstein, C.J., Gerstenblith, G.,
Coombs, V., Langenberg, P., Brinker, J.A., Resar, J.R. (2004) Angiology, 55(1), 1-8.
Paloshi, A., Fragasso, G., Piatti, P., Monti, L.D., Setola, E., Valsecchi, G., Gallucio, E., Chuichia, S.L., Margonato, A. (2004) Am. J.
Cardiol., 93(7), 933-935.
Kokate, C.K., Purohit. A.P., Gokhale, S.B. Pharmacognosy. 17th
edition. Nirali prakashan, Pune. pp. 540-545.
Adams, A.K., Wermuth, E.O., Mcbride, P.E. (1999) Am. Fam.
Physician, 60, 895-904.
The Heart Outcome Prevention Evaluation study investigators.
Effects of angiotensin converting enzyme inhibitor, Ramipril, on
cardiovascular events in high-risk patients. (2000) N. Engl. J. Med.,
342, 145-153.
Gey, K.F., Puska, P., Jordan, P., Moser, U.K. (1991) Am. J. Clin.
Nutr., 53(1 suppl), 326S-334S.
Verlangieri, A.J., Kapeghian, J.C., el-Dean, S., Bush, M. (1985)
Med. Hypotheses, 16, 7-15.
Riemersma, R.A., Wood, D.A., Macintyre, C.C., Elton, R.A., Gey,
K.F., Oliver, M.F. (1991) Lancet, 337, 1-5.

Nutraceuticals - An Emerging Era in the Treatment and Prevention


Luoma, P.V., Nayha, S., Sikkila, K., Hassi, J. (1995) J. Intern.

Med., 237, 49-54.
Bolton-Smith, C., Woodward, M., Tunstall-Pedoe, H. (1992) Eur.
J. Clin. Nutr., 46, 85-93.
Knekt, P., Reunanen, A., Jarvinen, R., Seppanen, R., Heliovaara,
M., Aromaa, A. (1994) Am. J. Epidemiol., 139, 1180-1189.
Stampfer, M.J., Hennekens, C.H., Manson, J.E., Colditz, G.A.,
Rosner, B., Willett, W.C. (1993) N. Engl. J. Med., 328, 1444-1149.
Rimm, E.B., Stampfer, M.J., Ascherio, A., Giovannucci, E.,
Colditz, G.A., Willett, W.C. (1993) N. Engl. J. Med., 328, 14501456.
Losonczy, K.G., Harris, T.B., Havlik, R.J. (1996) Am. J. Clin.
Nutr., 64, 190-196.
Hodis, H.N., Mack, W.J., LaBree, L., Cashin-Hemphill, L., Sevanian, A., Johnson, R. (1995) JAMA, 273, 1849-1854.
Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W, Dawsey S, Wang, G.Q.
(1993) J. Natl. Cancer Inst., 85, 1483-92.
Virtamo, J., Rapola, J.M., Ripatti, S., Heinonen, O.P., Taylor, P.R.,
Albanes, D. (1998) Arch. Intern. Med., 158, 668-675.
Rapola, J.M., Virtamo, J., Ripatti, S., Huttunen, J.K., Albanes, D.,
Taylor, P.R. (1997) Lancet, 349, 1715-1720.
Stephens, N.G., Parsons, A., Schofield, P.M., Kelly, F., Cheeseman, K., Mitchinson, M.J. (1996) Lancet, 347, 781-6.
Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A. (1996) N. Engl. J. Med,. 334, 1150-1155.
Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R. (1996) N. Engl. J. Med., 334, 1145-1149.
GISSI-Prevenzione, (1999) Lancet, 354, 447-455.
Hooper, L., Ness, A.R., Davey, Smith, G. (2001) Lancet, 357,
Asplund, K. (2002) J. Intern. Med., 251(5), 372-392.
Enstrom, J.E., Kanim, L.E., Klein, M.A. (1992) Epidemiology, 3,
Heitzer, T., Just, H., Munzel, T. (1996) Circulation, 94, 6-9.
Levine, G.N., Frei, B., Koulouris, S.N., Gerhard, M.D., Keaney,
J.F. Jr., Vita, J.A. (1996) Circulation, 93, 1107-13.
Brown, A.A., Hu, F.B. (2001) Am. J. Clin. Nutr., 73, 673-686.
Gaddi, A., Descovich, G., Noseda, G. (1984) Artherosclerosis, 501,
Salonen, J.T., Alfthan, G., Huttunen J.K., Pikkarainen, J., Puska, P.
(1982) Lancet, 2(8291), 175-179.
Kwiterovich, P.O. Jr. (1997) J. Am. Diet Assoc., 97(7 suppl), S3141.
Jialal, I. Micronutrient modulation of nonconventional risk factors
for CAD. In, The role of diet in reducing the risk of heart disease.
New York, McGraw-Hill, 1997, 13-20.
Sinatra, S.T. (1997) Mol Aspects Med., 18(suppl), S299-305.
Soja, A.M., Mortensen, S.A. (1997) Mol. Aspects Med., 18(suppl),
Law, M. (2000) BMJ, 320, 861-864.
Shrapnel, B., Simons, L. (2001) Curr. Therapeut., 42(3), 45-48.
Lichtenstein, A.H., Dekelbaum, R.J. (2001) Circulation, 103, 11771179.

Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 1



Cater N.B. (2000) Prevent. Cardiol., 3, 121-130.

Lichtenstein, A.H., Deckelbaum R.J. (2001) Circulation, 103(8),
FDA Talk Paper, FDA authorizes new coronary heart disease
health claim for plant sterol and plant stanol esters. Food and drug
administration U.S. department of health and human services.
William Charles Evans, Phenols and phenolic glycosides. Chapter
20. In, Trease and Evans; Pharmacognosy. Eds. W.C.Evans. 14th
edition. W.B.Saunders Company limited. pp. 251.
Rimm, E.B., Katan, M.B., Ascherio, A., Stampfer, M.J., Willett,
W.C. (1996) Ann. Intern. Med., 125, 384-389.
Hertog, M.G., Feskens, E.J., Hollman, P.C., Katan, M.B., Kromhout, D. (1993) Lancet, 342, 1007-1011.
Rimm, E.B., Katan, M.B., Ascherio, A., Stampfer, M.J., Willett,
W.C. (1996) Ann. Intern Med., 125, 384-389
Folts, J.D. (2002) Adv. Exp. Med. Biol., 505, 95-111
Hertog, M.G.L., Feskens, E.J.M., Hollman, P.C.H., Katan, M.B.,
Kromhout, D. (1993) Lancet, 342, 1007-1011.
Keli, S.O., Hertog, M.G.L., Feskens, E.J.M., Kromhout, S. (1996)
Arch Intern Med., 154, 637-642.
Anderson, J.W., Johnstone, B.M., Cook-Newell, M.E. (1995) N.
Engl. J. Med., 333, 276-282.
Anthony, M.S., Clarkson, T.B., Highes, C.L. Jr, Morgan, T.M.,
Burke, G.L. (1996) J. Nutr., 126, 43-50.
Giacomo, Spignoli. (2000) Eur. Bull. Drug Res., 8(1), 1-8.
Gibson, G.R., Roberfroid, M.B. (1995) J. Nutr., 125, 1401-1412
Kopp-Hoolihan L. J. (2001) Am. Diet. Assoc., 101(2), 229-238
Kaur, I.P., Chopra, K., Saini, A. (2002) Eur. J. Pharm. Sci., 15(1),
Roberfroid, M.B., Delzenne, N. (1998) Annul. Rev. Nutr., 18, 117143
Roberfroid, M.B., Van Loo, J.A.E., Gibson, G.R. (1998) J. Nutr.,
128, 11-19
Hasler, C.M. (2000) J. Am. Coll. Nutr., 19(5), 499S-506S.
Salminen, S., Bouley, C., Boutron-Ruault, M.C. (1998) Br. J. Nutr.,
80(Suppl), S147-171.
Smirnov, V.V., Reznik, S.R., Viunitskaia, V.A. (1993) Mikrobiolohichnyi Zhurnal, 55, 92-112.
Melnikova, V.M., Gracheva, N.M., Belikov, G.P. (1993) Antibiotiki i. Khimioterapiia, 38, 44-48.
Roberfroid, M.B. (2000) Am. J. Clin. Nutr., 71(6), 1682S-1687s.
Hosono, A. (2000) J. Dairy Sci., 83(8), 1705-1711.
Taranto, M. (1999) J. Dairy Sci., 83, 401-403.
Agerholm-Larsen, L. (2000) Eur. J. Clin. Nutr., 54(4), 288-297.
Jackson, T.G., Taylor, G.R.J., Clohessy, A.M. (1999) Br. J. Nutr.,
89, 23-30
Lin, S. (1989) J. Dairy Sci., 72, 2885-2899.
Lipid Research Clinics Program. The lipid research clinics coronary prevention trial results, Reduction in the incidence of coronary
heart disease. (1984) J. Am. Med. Assoc., 251, 351-363.
The National Heart, Lung, and Blood Institute. Reducing High
Blood Cholesterol. (1998) NIH Publication, 98, 3658.