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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5365_Библиотеки_им_академика_М_И_Перельмана
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Biomarkers as Targeted Herbal Drug Discovery
herbal drugs. Converting herbal drugs to the nanoscale delivery system using
various fabrication approaches can result in the improvement of many pharmacokinetic profiles as well as in vivo stability and controlled absorption of
the drug at the desired site. Aim of the present review is to focus on many
facts related to cardiovascular diseases (CVDs) and the role of herbal drugs
in treatment with nanotechnology driven delivery system.
In the history of the health care system, cardiovascular diseases (CVDs) are
one of the most serious concerns and are emerging as a worldwide threat. It
includes many diseases such as myocardial infarction, angina, chronic heart
failure (CHF), stroke, hypertension (HTN), arrhythmia, hyperlipidemia,
hardening of the arteries, and many more circulatory system disorders. In
recent studies, it has been found that in the United States (US) every 33
seconds claims one death due to CVDs (Heart Disease and Stroke Statistics,
2018). Even 40% of total annual deaths are caused by only CVDs. As far
the global effects of CVDs are concerned it is found to be the leading cause
of death and accounted for around 18 million deaths per year in 2015 which
is expected to increase to 23.6 million by 2030 (Heart Disease and Stroke
Statistics, 2018). Despite of having highly developed health care systems,
till date cardiovascular system-related diseases poses a major challenge and
need proper investigation of related factors.
It can be well understood that a health care problem related to heart and
circulatory systems will have innumerable reasons such as diet, obesity,
lifestyle, genetics, etc. Amongst all these, nowadays in developed as well
as in developing countries diet and obesity are two of the major factors for
various non-communicable diseases, primarily including many of the CVDs.
In many proofs of concept studies related to diet and obesity both in
developed countries like US and UK (United Kingdom) and developing
countries such as India, it has been found that these two factors play a major
role in inducing various cardiovascular disorders either directly or indirectly
(Yusuf et al., 2001; Eilat-Adar, 2013; Kochar et al., 2011; Lavie et al., 2009;
Shabana and Vijay, 2010).
Food consumption is an unique and classied habit of various categories
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of population depending on the availability and geographical conditions. As
far as the basic ingested food is concerned, it is same in terms of chemistry
such as fat, carbohydrate, and many other energy supplements. However,
there are innumerable controversies related to the diet system which further
leads to various aspects of health. Undoubtedly, there has been a great
change worldwide in food systems since lifestyle change has occurred
rapidly throughout the modern world. Processed and packaged foods are
having a major contribution in this change (Ng et al., 2012). This tradition
of the packaged food system has vastly increased the caloric supply and
in parallel provides low-cost feed to livestock which further induces cheap
inputs in processed foods mainly for proteering (Connor and Schiek, 1997).
It is also a fact that these packaged and processed foods contain various
unsaturated fats and other materials, long term intake of which can trigger
CVDs, mainly atherosclerosis (Eman et al., 2012; Reddy and Katan, 2004).
Now with all recent innovative technologies of food processing and easy
availability from farm to fork, there is a signicant enhancement of food
consumption of various qualities (Welch and Mitchell, 2000; Fellows, 2009;
Burch and Lawrence, 2007). It has also been found in some recent studies
that the production of foods from animal sources has been increased multiple
times as compared to coarse grains and other natural veggies such as roots,
legumes, etc. (Schaffer, Hunt, and Ray, 2007; Weis, 2013).
Now if we consider all the above factors it might be easier to understand the relation between food habits and cardiovascular and other clinical
precipitates both in developed and developing nations. As the major basic
food, constituents are the same across the globe, the consumption and effect
of the same can be generalized depending on many proof of concept studies
and various eld works. As an outcome of various studies, it can be observed
that fruit-rich diets, unrened grains, vegetables, dairy products of low-fat
content, and a diet containing low saturated fats and sodium can result in
lowering CVDs (Aldana et al., 2007). Diets containing mono and polyunsaturated fats, sterols from plant sources, brans, various nuts, soy proteins,
isoavones, etc., are found to be benecial for the health of the heart and
reduces various risk to CVDs (Frank et al., 2006; Jensen et al., 2004). On
other side diets containing trans-fat, added sugar, rened grains, red meat,
and processed meat, etc., can accelerate cardiovascular risk enhancing
factors (Mensink et al., 2003; Pan et al., 2013; Micha, Michas, and Mozaffarian, 2012).
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Obesity also has an indistinguishable role towards many of the CVDs.
An unhealthy lifestyle and nutritional disorders can lead to obesity and it
further precipitates diverse clinical situations such as atherosclerosis, renal
disorders, HTN, etc. (John et al., 2002). Many circulatory system disorders
can be possibly caused by obesity such as diabetes and dislipidemia which
further leads to stiffness of blood vessels and stroke like conditions. So diet
and obesity or both of these in combination (which happens frequently in a
sedentary lifestyle) can lead to many serious cardiovascular disorders.
Now as these CVDs are getting generalized and emerging to be a
common health care problem, in long term, management of these diseases is
a challenge and demands best screening processes related to medicines and
various other factors. Science and technology has introduced innumerable
active pharmaceutical ingredients for prevention and cure of more or less all
CVDs. These active moieties can be categorized as antihypertensive, antianginal, antiarrythmic, diuretics, blood thinning, antioxidants, etc. In spite
of many complex clinical conditions, these agents are found to be successful
in manifestation of CVDs. But it has also been observed that in the long term
these synthetic drugs can precipitate some undesired effect which further
compels us to think of other options.
Inspite of lacking signicant data related to clinical effects many herbal
cardiovascular agents are proven to be comparatively safer than synthetic
agents and can be used as an alternative to many synthetic drugs (Nick et
al., 1998). Unlike the synthetic medicinal drugs, the herbal drugs exert very
little, if any adverse effects. Adverse effects of synthetic drugs is a potential
threat and according to a study about 8% of hospital admission in America
is due to adverse effect of the drugs (Karimi et al., 2015). However, toxicity
of any herbal drug can be possible due to misidentication (Karimi et al.,
2015). As Herbal drugs have been used in medical treatments since the times
of ancient civilizations, various drugs have become the mainstay of human
pharmacotherapy. In cardiovascular system, herbal drugs are used in many
disorders such as congestive heart failure (CHF), angina pectoris, atheroscle-
rosis, cerebral insufciency, systolic HTN, venous insufciency (Nick et al.,
1998) (Figure 6.1).
In the list of available herbs for such disorders, there are many sources such
as Commiphora mukul, Crataegus oxycantha, Inula racemosa, Terminalia
arjuna, digitalis, garlic, etc. In many research works related to CVDs many
137 Delivery of Herbal Cardiovascular Drugs in the Scenario of Nanotechnology
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Various CVDs risk factors and links among them.
other herbs are being noticed to be useful for various CVDs (Jahan et al.,
2016; Rachel and Michael, 2009). Many of the traditional herbs are also
used in diet for betterment of heart as well as to reduce obesity (Hannah and
Parameswari, 2010). The mechanism of action of these herbs and natural
ingredients for keeping a heart-healthy may differ from product to product
and sometimes exert multiple effects in a way to modulate cardiovascular
system (Frishman, Sinatra, and Moizuddin, 2004). Ginger, garlic, curcumin,
black pepper, coriander, and cinnamon are natural herbs which are used for
a good cardiac health. Apart from the other global claims of these herbs, in
traditional Indian system, i.e., Ayurveda, and Siddha all these species of herbs
are described as medicinal plants for cardiac health and having properties
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such as antithrombic, hypolipidemic, antiatherosclerotic, etc. (Srivastava,
Bordia, and Verma, 1995). A brief description of these medicinal herbs can
be given as follows:
1. Garlic: It is well known as Allium sativam and believed to be
originated from Central Asia. Garlic is used worldwide as a food
ingredient mainly as flavoring agent to enhance physical and mental
health. As a cardiovascular agent, garlic is claimed to prevent heart
diseases and can also be used as a heart tonic by maintaining the
fluidity of heart (Fenwick and Hanley, 1985; Mykolas, 2009). Garlic
as a part of diet or alone is advocated to exert a positive role in
preventing or delaying the CVDs by reducing blood lipid content
by inhibiting enzymes involved in lipid synthesis, decreasing plate
lets aggregation, reducing HTN, preventing lipid per-oxidation of
oxidized erythrocytes and inhibiting angiotensin converting enzymes
(Rahman, 2001; Khalid et al., 2006).
2. Ginger: It is well known as Zingiber officinale and belongs to
family Zingiberacae. Ginger is a very famous herbal medicine and
is commonly used in Chinese, Tibb-Unani, and Ayurvedic herbal
medicinal system. Since ancient age ginger is a part of diet and
supposed to be useful for a wide range of health effects such as
rheumatism, arthritis, sprains, muscular aches, pains, sore throats,
cramps, HTN, constipation, indigestion, vomiting, dementia, fever,
infectious diseases and helminthiasis (Ali et al., 2008). As far as
the cardiovascular effects of the ginger are concerned, in an experi
mental study ginger is noticed to decrease coronary artery diseases
by significant reduction in platelet aggregation (Bordia, Verma, and
Srivastava, 1997). In a different proof of concept studies on various
kinds of animals like rabbits and rats it has been concluded that
ginger and its extracts can be useful for maintaining the lipid profiles
(Sharma, Gusain, and Dixit, 1998; Bhandari, Kanojia, and Pillai,
2005).
3. Cinnamon: It is extensively used spices of India, Sri Lanka,
Australia, Egypt, and China. The leaves and bark of cinnamon
is used to produce essential oil (EO). The EO is believed to have
some cardiovascular effects (Kawatra and Rathai, 2015). Cinnamon
extracts are found to decrease cholesterol synthesis by inhibiting
HMG-CoA reductase, an enzyme which catalyzes cholesterol
biosynthesis. Cinnamon by activating PPAR
results in improved
ү
insulin resistance which further reduced fasted LDL-c, and managed
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obesity-related hyperlipidemia and also increased NO levels, which
acts as a potent Vasodilator (Kamal, Thanaa, and El-Twab, 2009).
4. Coriander: It is one of the most common spices used in India. Cori-
andrum sativam or coriander as a traditional drug has a long history.
In cardiovascular health, coriander is used to decreased cholesterol
and lipid. Even it has been reported that the coriander is responsible
for a significant decrease of LDL and VLDL and enhancement of
HD L. Thus, in overall effect, Coriandrum sativam is responsible for
good cardiac health.
Other than these all herbal medicine turmeric, black pepper, etc., are also
found to improve cardiac health and useful in CVDs.
There are innumerable allopathic drugs available for the management of
many serious cardiovascular disorders and many of the CVDs are chronic
in nature. In the same context if we consider the safety of entire human
physiology it will be better to consider that use of allopathic system can be
a need of emergency but if we have time then there are other better ways
such as treatment with herbal medicines. As far as the herbal medicines are
concerned other than the above-mentioned herbal products there are many
other herbs, extract, or parts of the same which can be used as medicine
for the treatment of many acute or chronic CVDs like HTN, CHF, atherosclerosis, cerebral, and peripheral vascular disease, angina pectoris, venous
insufciency, arrhythmia, etc. Various medicinal plants such as Crataegus
oxycantha, Rauwola serpentina, Inula racemosa, Terminalia arjuna,
Commiphora mukul, Digitalis, Astragalus, Aesculus hippocastan, Ginkgo
biloba, etc., are found to be useful for many cardiovascular disorders. Each
of these herbs has their own property for treating CVDs.
Many herbs are found to contain potent cardioactive glycosides having
serious cardiovascular effects showing positive inotropic actions. Digitalis
purpurea is one of the famous herbs containing cardioactive glycosides used
successfully for cardiac arrhythmia leading to CHF since many decades.
Digoxin and Digitalis are the responsible cardioactive glycosides found in
Digitalis pupurea. Digitalis lanata contains only digoxin. As a drawback of
the drug, the therapeutic index of digitalis and digoxin is very low which
makes the dose of the drug a subject of concern (Amine et al., 2016).
Another famous herb used for cardiovascular disease mainly for HTN is
Rauwola serpentina. The root of Rauwola is used for this purpose. The
main responsible drug used as antihypertensive is Reserpine. It was one
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of the most famous drugs used on a large scale in that period of time as
a systemic antihypertensive. Mechanism of action of reserpine as antihypertensive includes decrease in vascular peripheral resistance and cardiac
output, lowering heart rate as well as decreasing renin secretion (Charles et
al., 1963).
Panax ginseng is also an important source of drug from herbal arena used
for CVDs mainly HTN, myocardial ischemia and dyslipidemia. Ginseng is
one of the older and traditional drugs used from natural sources. Part of the
ginseng responsible for the drug action is known as ginsenoside. As far as
the pharmacological actions are concerned as there are innumerable types of
ginsenoside identied, it may have various pharmacological actions involve
in the therapy. About 40 ginsenosides has been identied till 2012 depending
on the method of separation and analysis (Fuzzati, 2004). In a proof of
concept study, it has been found that the Korean red ginseng increases blood
pressure (BP) in case of low BP while it works as an antihypertensive in the
condition of higher BP (Jeon et al., 2000).
Breviscapine is one of the most signicant drugs used for the treatment
of cardiovascular and cerebrovascular disorders. It is a crude extract of many
avonoids of Erigeron breviscapus (Vant.). Hand.-Mazz., containing at least
85% of scutellarin, which is a famous traditional herbal drug used in China
as a cerebrovascular medicine to improve cerebral blood supply. According
to various in vivo and in vitro proofs of concept studies, it has been observed
that breviscapine exerts a wide range of cardiovascular pharmacological
effects, such as vasodilation, anticoagulat, antithrombotic, endothelial
protector. Apart from that, it helps to reduce smooth muscle cell migration
and proliferation and helps in anticardiac remodeling, antiarrhythmia, and
blood lipid reduction. Further many clinical studies have reported that
breviscapine could be used in conjunction with Western medicine for CVDs
including coronary heart disease, myocardial infarction, atrial brillation,
HTN, viral myocarditis, hyperlipidemia, pulmonary heart disease, and
chronic heart failure.
Many other herbal drugs which are used as drugs for various CVDs can
be seen as given in Table 6.1.
Regardless of having so many herbal drugs for variety of cardiovascular
disorder both for acute and chronic in nature there are, many issues related
to dose and efcacy of the drugs along with some toxicological concerns.
These all herbal drugs are limited to their respective clinical manifestation
because of their high dose and related toxic effects. Therefore, to overcome
these problems and to make the herbal drugs more clinical signicant,
141 Delivery of Herbal Cardiovascular Drugs in the Scenario of Nanotechnology
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nanotechnology is a real need. This nanosized dependent technology where
it is dened as techniques aimed to conceive, characterize, and produce material at the nanometer scale, represent a fully expanding domain, where one
can predict without risk that production and utilization of nanosize materials
will increase exponentially in near future.
TABLE 6.1 Herbal Drugs Used in Cardiovascular Disease
Sl. Herbal Source Cardiovascular Use References
No.
1. Asian ginseng Hypertension,
hypercholesterolemia
2. Astragalus Hyperhomocysteinemia,
vascular protection
3. Flaxseed oil Hypercholestrolemia Rodriguez-Leyva et al.,
4.
Grape (Vitis
vinifera) seeds
5. Hawthorn Mild to moderate heart failure
6. Black pepper Hypolipidemic effect,
7.
Inula racemosa
8.
Terminalia arjuna
Atherosclerosis, hypertension,
hypercholesterolemia, chronic
venous insufficiency
(NYHA I-II).
myocardial infarction, pressure
overload-induced hypertrophy.
Cardiac ischemia, pressure
overload-induced hypertrophy
Cardioprotective,
hypercholesterolemia
Catherine et al., 2006
QIU et al., 2017
2010; Ankit et al., 2014
Mustali and Joseph, 2009
Mary et al., 2010
Shenuarin and Fukunaga,
2009
Chabukswar et al., 2010
Shridhar, 2007
On conversion to nanoscale the surface area of parent molecule increases
to a great extent which enables the formulation to achieve signicantly
enhanced pharmacokinetic parameters such as solubility, permeability, and
hence bioavailability.
In recent decades with the help of many proofs of concept studies, it has
been proven that herbal drug delivery using nanotechnology is better than
the conventional herbal deliveries.
In the process of establishment of therapeutic efficacy and safety of herbal
drugs, clinical studies are either not performed or scant from the studies.
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Biomarkers as Targeted Herbal Drug Discovery
In recent studies, it has been observed that in-spite of being therapeutically
active many herbal drug shows clinical limitation and precipitates various
toxicity problems depending on the dose and dosage of the drug. Many of
the herbal drugs which are useful in various cardiovascular therapies are
drawing attention towards their clinical use due to low therapeutic index
which further signifies the dose of the drug and indicates the need of novel
delivery system.
DELIVERY PROBLEMS
Novel drug delivery systems are emerging to be a necessity for herbal
medicinal system for the purpose of increasing the efficacy of drug and
reducing the side effects of many herbal compounds. The integration of the
novel drug delivery system and innumerable herbal medicines is supposed
to combat more serious diseases. Since decades regardless of established
therapeutic and pharmacological effects, herbal medicines were not considered for the development of novel formulations due to lack of scientific
justification and processing difficulties, like, extraction, standardization, and
identification of individual drug components in mixed polyherbal systems.
However, with the help of newer outcomes in research and technology in
phytopharmaceutical field it seems to solve the problems related to delivery
of herbal medicines and other pharmacokinetic problems such as determination of pharmacokinetics (PKs), mechanism of action, site of action, accurate
dose required, etc., by incorporating the drugs in novel drug delivery system,
such as microemulsions, nanoparticles, solid dispersions, matrix systems,
liposomes, solid lipid nanoparticles (SLNs), etc. Recently used novel drug
delivery systems for the incorporation of herbal drugs and compounds can
be briefly described as:
1. Liposome: These are nanosized spherical lipoidal delivery systems
capable of entrapment and delivery of both hydrophilic and
hydrophobic drug candidates because of its specialized structural
characteristics. Liposomal vesicles may composed of natural and/
or synthetic surface active agents like phospho or sphingo-lipids.
These are natural surfactant and can arrange themselves in tail to tail
manner forming a bilayer flexible membrane containing some water.
Liposomes can vary from 0.5 µ to 5 µ in size and are unique delivery
system for drugs with highly variable lipophilicities. Liposomes with
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herbal drug are known as herbosomes. In CVDs, herbosomes can be
used as a potential delivery system (La Grange et al., 1999). Other
than herbosomes these systems are also known as planterosomes.
In this word, planterosomes ‘plantero’ stands for herb and ‘some’
stand for cell-like structure. These are the novel formulation which
offers comparatively significant and better bioavailability of hydro
philic herbal drugs and flavonoids and are absorbed through skin
or gastrointestinal tract. Here the phosphatidylcholine molecules in
the herbosomal or planterosomal complex act by pushing the phyto
chemical constituents through the outer membrane of gastrointestinal
epithelial cells which further enters into the bloodstream (Athira et
al., 2014).
2. Microemulsion: According to the definition of Danielsson and
Lindman, “a microemulsion is a system of water, oil, and an amphi
phile which is a single optically isotropic and thermodynamically
stable liquid solution.” These are transparent or translucent formu
lation and categorized as water in oil (w/o) or oil in water (o/w)
systems in the size range of 5 to 50 nm (Danielsson and Lindman,
1981). Microemulsion system is usually much different than emul
sion (with a size range of >0.1 µm) and nanoemulsion (thermody
namically unstable). According to IUPAC, in an emulsion liquid
droplets and/or liquid crystals, are dispersed in a liquid. So As for the
characteristics of the microemulsion is concerned, microemulsion is
excluded from this definition if the word “dispersed” is explained as
non-equilibrium and opposite to “solubilized,” a term which can be
applied to microemulsion and micellar systems. Unlike microemul
sion, the latter ones are not thermodynamically stable.
3. Nanoemulsion: In recent decades, the branch of science dealing with
fast screening of material and unique ability of combinatorial chem
istry has gifted the idea of nanoemulsion formulation. Approaches
for nanoemulsion remain more or less similar in comparison to
microemulsion. It also requires a synthetic and/or natural oil, with
surfactants and co-surfactants for fabrication into an oil in water
(o/w) or water in oil (w/o) emulsion system having a droplet size
of 5 to 500 nm (Kale et al., 2017). The membrane stability and flex
ibility of the system come as the result of the used surfactant and
co-surfactant mixture. Nanoemulsion is thermodynamically unstable
but has long term kinetic stability. The drug loading (DL) capacity
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