Figure 2.13: Structures of Aspirin (adapted from Neault et al., 2000)
2.10.2
Clopidogrel
Clopidogrel (Figure 2.14) belongs to the thienopyridine class of antiplatelet agents. It is
widely used to prevent heart attacks, cerebrovascular diseases and coronary artery
disease (Anderson et al., 2010). Clopidogrel irreversibly inhibits P2Y
12
receptors, thus
reducing the activity of adenosine diphosphate (ADP) as an agonist in platelet
aggregation (Duerschmied et al., 2010). Clopidogrel can serve as an alternative
antiplatelet drug for patients with aspirin-induced gastric ulcers (Chan et al., 2005).
Clopidogrel is a prodrug; it is metabolized to its active form in the liver by cytochrome
P450 2 C19 (CYP2C19) to serve as an antiplatelet agent. The CYP2C19 enzymes are
among the superfamily of cytochrome p450. They are monooxgenases that play a
crucial role in xenobiotic and lipid metabolism (Mistry et al., 2011).
Clopidogrel has been associated with adverse side effects such as thrombocytopenia
purpura and hemorrhaging (Zakarija et al., 2004). This drug interacts with proton pump
inhibitors such as esomeprazole or omeprazole, thereby reducing the antiplatelet
potential. Clopidogrel exhibits less antiplatelet aggregation effects on patients who are
on proton pump inhibitors (John and Koshy, 2012). Studies indicate that patients with
pulmonary arteriosclerosis show aspirin resistance and clopidogrel might be the best
alternative antiplatelet agent (Diehm et al., 2004).
2-55
Figure 2.14: Structure of Clopidogrel (adapted from Shaw et
al
., 2015)
2.10.3 Dipyridamole
Dipyridamole (Figure 2.15) is a drug with vasodilator and antiplatelet properties, derived
from pyrimidopyridine. Dipyridamole inhibits the activities phosphodiesterase, enzymes
that break down cAMP. This increases the intracellular level of cAMP and reduces the
binding affinity of ADP to its receptor to initiate platelet aggregation. The drugs also
plays a crucial role in triggering the release of prostaglandin (PGI
2
) from the endothelial
cells and inhibit the reuptake of adenosine by platelets, endothelial cells and red blood
cells leading to an increase of adenosine in the extracellular matrix (Sudlow,2005).
Dipyridamole is used to lower pulmonary hypertension without a change in systemic
blood pressure (De Schryver, 2003). The drug has been implicated in preventing the
release of pro-inflammatory cytokines (MMP-9, MCP-1) and in the inhibition of smooth
muscle proliferation (Dixon et al., 2009).
Dipyridamole absorption into the gastrointestinal tract is pH-dependent, therefore the
use of proton pump inhibitor in the treatment of a gastric ulcer might prevent absorption
(Derendorf, 2005). Dipyridamole is usually used along with aspirin as a dual therapy to
effectively combat transient ischaemic attacks and stroke (Halkes et al., 2006). In a
recent study, stroke patients treated with dipyridamole showed a significant reduction in
thrombotic episodes when compared with a control. In addition, the combination of
dipyridamole and aspirin showed a more significant reduction in thrombotic episodes in
comparison to dipyridamole alone (Leonardi-Bee et al., 2005).
2-56
Figure 2.15: Structure of Dipyridamole (adapted from Lin and Buolamwini, 2007)
2.10.4 Ticlopidine
Ticlopidine (Figure 2.16) is an antiplatelet agent in the family of thienopyridine. It inhibits
ADP receptors on platelet membranes. This prevents the activation of glycoprotein
llb/llla integrins which increases the binding affinity of fibrinogen to platelets. It is
commonly used in patients who do not tolerate aspirin and clopidogrel. However, the
drug is implicated in the onset of neutropenia and aplastic anaemia (Bortolotti et al.,
2002).
Ticlopidine, in combination with aspirin as a dual therapy, is found to be more effective
in the treatment of recurrent vascular episodes in patients with vascular diseases (Tran
et al., 2004).
2-57
Figure 2.16: Structure of Ticlopidine (adapted from Quinn and Fitzgerald, 1999)
2.10.5 Cilostazol
Cilostazol (Figure 2.17) is a derivative of quinolinone which is commonly used as an
antiplatelet, vasodilator and anti-thrombotic (Chapman et al., 2003). Cilostazol is
reported to relieve intermittent claudication in patients with peripheral vascular diseases
(Robless et al., 2008). Cilostazol selectively inhibits phosphodiesterase-III (PDE3) which
increases the level of cAMP in the extracellular matrix. This leads to an increase in
activated protein kinase A (PKA) which prevents platelet aggregation by reducing
calcium mobilization from the saroplasmic reticulum. PKA also inhibits the activation of
myosin light-chain kinase, the enzyme responsible for vasoconstriction, thereby exerting
vasodilatatory effects. The main function of cilostazol is the vasodilation of the arteries
of peripheral and anti-platelet aggregation. The drug was reported to improve walking
distance and cardiovascular episodes in patients with a stable inspiratory capacity
(Storey, 2002).
Cilostazol is well tolerated, but has unexpected side effects such as headaches,
palpitations, increased heart rate, rhinitis, diarrhea, peripheral oedema and abnormal
stool (Barnett et al., 2004).
2-58
Figure 2.17: Structure of Cilostazol (adapted from Basniwal et al., 2010)
2.10.6 Sarpogrelate
Sarpogrelate (Figure 2.18) is a drug that acts as an antagonist at serotonin receptors
(5HT2A and 5HT2B) thereby inhibiting platelet aggregation induced by serotonin
(Muntasir et al., 2007). In mammals, the drug is metabolized to (R-S)-1-[2-[2-(3-
methoxyphenyl)ethyl[phenoxy]-3-(dimethylamino)-2-propanol-M-1through the hydrolysis
of its succinate ester moiety in the liver (Saini et al., 2004). Serotonin plays an
important role in the onset of atherothrombosis. The stored serotonins in the dense
granules of platelets are released during platelet activation. This stimulates smooth
muscle proliferation, endovascular contraction and subsequent thrombus formation,
which may lead to vessel occlusion (Nishihira et al., 2006). Sarpogrelate was
demonstrated to improve endothelial function in patients with peripheral arterial
diseases after oral administration for 12 weeks (Miyaza et al., 2007).
2-59
Figure 2.18: Structure of sarpogrelate (adapted from Park et al.,
2010
)
2.10.7 GPIIb/IIIa Receptors Antagoinst
GPIIb/IIIa Receptors are found on the platelet membrane. They are triggered during
platelet activation to bind fibrinogen or VWF and form crosslinks with platelets which are
the common final pathway to platelet aggregation (Auer et al., 2003). GPIIb/IIIa receptor
antagonists are divided into three classifications: monoclonal anti-body fragments
(abciximab), peptide inhibitors (eptifibatide) and non-peptide inhibitors (lamifiban and
triofiban) (Auer et al., 2003). These drugs are appropriate for diabetes and renal related
diseases, but unsuitable for patients scheduled for surgery due to prolonged bleeding
(Tcheng et al., 2003).
2.10.8 Picotamide
Picotamide (Figure 2.19) is an antagonist of the thromboxane A
2
receptor (TXA
2
) and
prostaglandin H (PGH
2
). It is a derivative of methoxy-isophtalic acid and has been
reported to inhibit thromboxane A2 synthase (Neri- Sereneri et al., 2004). The efficacy
of picotamide as an antiplatelet is attributed to its dual action, which includes the
inhibition of platelet aggregation and the increase in production of antiplatelet
aggregation and prostaglandins such as prostaglandin I2 (PGI2) (Gresele et al., 1991).
Picotamide was reported to significantly reduce the mortality rate (to 23%) in patients
with peripheral arterial diseases when compared to a placebo (Balsano et al., 1993).
2-60
Figure 2.19: Structure of picotamide (adapted from Modesti et al., 1993)
2.10.9 Beraprost
Beraprost (Figure 2.20) is an orally administered drug analogue, with similar
pharmacodynamic properties to prostaglandin I
2
(PGI
2
) (Melian et al., 2002). The
beraprost mechanism of action includes: vasodilation, which leads to lower blood
pressure; dispersion of abnormal platelet aggregates; and the disruption of platelet
aggregation (Nishio et al., 2001). Beraprost binds to PGI2 receptors on the platelet
membrane. This stimulates production of the adenylate cyclase and guanylate cyclase
which increase the levels of cAMP and cyclic guanosine monophosphate (cGMP),
respectively. The cAMP and cGMP inhibit calcium influx into the transmembrane from
the intracellular matrix. This process leads to the relaxation of the smooth muscle cell,
thereby initiating vasodilaton (Melian et al., 2002). Beraprost is an appropriate drug for
pulmonary hypertension and for the reperfusion of injured patients (Barst et al., 2003).
Figure 2.20: Structure of Beraprost (adapted from Morrison et al., 2010)
2-61
2.10.10 Trapidil
Trapidil (triazolopyrimidine) (Figure 2.21) is an antiplatelet drug widely used to reduce
restenosis after percutaneous coronary angioplasty (Maresta, 1994). Trapidil is a
platelet derived growth factor antagonist (PDGF) and thus serves as a vasodilator.
PDGF is triggered during vascular injury and plays a crucial role in smooth muscle cell
proliferation, extracellular matrix formation and inflammatory cell chemotaxis. Trapidil
was demonstrated to reduce the incidence of cardiovascular episodes and to improve
the prognosis in cardiovascular diseases (Hirayama et al., 2003).
Figure 2.21: Structure of Trapidil (adapted from Vijaya et al., 2013)
2.11 Recent developments in platelet aggregation inhibitors
Explortation of medicinal plants extract as antiplatelet agents have gain new frontline in
pharmaceutical research. Some of the recent investigated antiplatelet aggregation
potential of medicinal plants include; ginisenosides isolated from processed ginseng
(Lee et al., 2010); flavonoids from Leuzea carthamoides (Koleckar et al., 2008); sulfur
containing compounds extracted from Scorodocarpus borneensis (Lim et al., 1999);
non
–
glycosidic iridoids from the leaves of Canpsis grandifora (Jin et al., 2005);
aporphine alkaloids isolated from leaves of Magnolia obovata (Pyo et al., 2003);
crude extracts of Euchresta formosana (Lo et al., 2003); phenolic and furan type
compounds isolated from Gastrodia elata (Pyo et al., 2004); extracts of Cinnamomum
2-62
cassia (Kim et al., 2010); amides isolated from Pipe taiwanese (Chen et al., 2007);
and dihydrochalcones isolated from the leaves of Muntingia calabura (Chen et al.,
2007); Pentacyclic triterpenoids (Oleanolic, Hederagerin, Ursolic acid, Tormentic acid
Myrianthic acid) isolated from the leaves of Campsis grandiflora (Jin et al., 2010).
2.12 Medicinal plants in traditional medicine
World Health Organization (WHO) defines traditional medicine as the sum total of skills,
practices and knowledge based on experiences, beliefs, and theories indigenous to
various cultures that are used to diagnose, prevent and treat any forms of ailment
(WHO, 2009). Several known medicinal plant species currently used today have been
part of traditional medicine going as far back as 2000 BC (Holt and Chandra, 2002). In
most developing countries, the use of traditional medicine among the people is based
on availability and affordability (Payyappallimana, 2010). The WHO estimates that 80%
of the world populace depends on medicinal plants for their basic health care (George
et al., 2001).
Africa is reported to be endowed with enormous medicinal plant resources. It is
estimated that over 500,000 species can be found in forest regions alone (Farnsworth et
al., 1985). A large number of scientific publications are made available on the uses of
some medicinal plants (Hutching et al. 1996; Opoku et al., 2002; Iwalewa et al., 2007;
Bibhabasu et al.,2008, Baccelli, 2010; Fasola, 2011; Osunsanmi et al., 2015).
A large proportion of modern drugs are derived from medicinal plants (Govaerts, 2001;
Thorne, 2002). Medicinal plants are therefore the best source for new drug discovery
(Anthony, 2005). For example, Cinchona succiruba yields quinine, an important source
of antimalalrial (Fabiano-Tixier et al., 2011); Rauwolfia vomitoria produces reserpine, an
antihypertensive and tranquilizer (Yu et al., 2013); the Calabar bean yields serine or
physostigmine, which is used in the treatment of ophtalamia diseases (Triggle et al.,
1998); Chrysanthemum cinerariifolium produces pyrethrins, which are used as
insecticide (Bradberry et al., 2005); Zingiber officinale produces gingerol, which is used
as a carminative (Ghosh et al., 2011); Agave sisalana produces hecogenin, which is
used in contraceptives (Elujoba, 2005).
2-63
Medicinal plants produce chemical compounds called secondary metabolites, such as
phenol, saponin, alkaloid, flavonoid and others (Tapsell et al., 2006). These secondary
metabolites protect the plants against the attacks of predators and also play an
important role in their biological activities. The secondary metabolites are also used to
fight a wide range of human diseases. Over 12 000 compounds have been isolated
from medicinal plants (Tapsell et al., 2006). Herbal medicines do not differ from modern
drugs in their mechanisms of action. This is based on the fact that the chemical
compounds in medicinal plants mediate their effects on the human body in a manner
identical to modern drugs. This makes herbal medicine as effective as modern drugs
(Lai et al., 2004). Over 122 of the chemical compounds identified by scientific
researchers are derived from medicinal plants and used in modern drugs (Fabricant et
al., 2001).
2.13 Triterpenoids
Triterpenes are a class of natural compounds consisting of sterols and steroids. They
are abundantly found in plants and animals. Most triterpenes consist of a C-30 carbon
skeleton and are biosynthesized from squalene (Figure 2.22). Most triterpenes are
produced from squalene through cyclization, ring expansions and molecular losses. An
example of such triterpenes is cholesterol (Figure 2.23). There are over twenty groups
of triterpenes.
2-64
The cyclization of squalene in a chair boat conformation produces the protostane cation.
Lanostrane (Figure 2.24), derived from this cation, forms most of the precursor of
steroids found in animals, whereas cycloartane (Figure 2.25), derived from a cation by
cyclization between C9-C19, forms most of the terpenoids in plants (Buckingham,
1996). These triterpenoids are widely called phytosterol (Buckingham, 1994).
Figure 2.22: Structure of squalene (Buckingham, 1994)
Figure 2.23: Structure of Cholesterol (Buckingham, 1994)
Figure 2.24: Structure of
Lanostrane(Buckingham, 1994)
Figure 2.25: Structure of Cycloartane
(Buckingham, 1994)
2-65
Over 2500 triterpenes have been investigated for their biological and pharmacological
activities. These include antimicrobial, antimutagenic, anti-inflammatory, anti-hiv,
antitumor and anticancer activities (Connoly et al., 2008, Zaidi et al., 2005, Lin et al.,
2003, Qian et al., 2007). The activities of some triterpenes were demonstrated to inhibit
the action of multi-drug resistance (Molnar et al., 2006). Tanachatchairatana et al.,
(2008) demonstrated that a triterpene esterified by cinnamic acid inhibited the activities
of Mycobacterium tuberculosis.
2.14 Betulinic acid
Betulinic acid (Figure 2.26) is found in the outer bark of several species of plants, but is
common in the white birch ( Betula pubescens) from where its name is derived. It yields
up to 22 % dry weight (Tan et al., 2003). Betulinic acid is among the naturally occurring
classes of pentacyclic triterpenoids which reportedly show anti-neoplastic (Fulda et al.,
1999), anti-angiogenesis (Mukherjee et al., 2004), antiplasmodial (Ziegler et al., 2004)
antiretroviral (Huang et al., 2006; Qian et al., 2007), anti-viral (Parlova et al., 2003;
Baltina et al., 2003), antioxidant, anti-tumour, anthelmintic, anti-inflammatory and
antiplatelet (Mukherjee et al., 1997; Liu et al., 2004; Habila et al., 2011; Habila et al.,
2013) activities.
HO
CH
3
CH
3
CH
3
H
CO
2
H
H
CH
3
H
3
C
H
3
C
CH
2
H
Figure 2.26: Structure of Betulinic acid (adapted from Osunsanmi et al., 2015)
2-66
2.15 Melaleuca bracteata
Melaleuca bracteata is a genus in the myrtle family Myrtaceae with fine scented foliage
and profuse white flowers appearing in all seasons. It is commonly called black tea tree,
paper bark, river tea tree, punk tree, honey myrtle, golden bottle brush, snow in the
summer tree, and white cloud tree. There are well over 2000 recognized species, most
of which are endemic to Australia (Craven, 2008). Melaleuca bracteata var. revolution
gold (Figure 2.27) is widely found in South Africa where it is commonly referred to as
Johannesburg gold. These species are shrubs and trees growing from 2 - 30 m tall,
often with exfoliating bark. The leaves are evergreen, alternately arranged, ovate to
lanceolate, 1- 25 cm long and 0.5 - 7 cm broad with an entire margin, dark green to
grey-green in colour. The flowers are produced in dense clusters along the stems, each
flower has a small petal and a tight bundle of stamens about 7- 8 mm long fused into
five bundles (each containing about 20 stamens) opposite the petals; flower colour
varies from white to pink, red, pale yellow or greenish. The fruit is a small capsule about
2 - 3 mm in diameter containing numerous minute seeds about 0.5
–
0.8 mm long. The
fruits aggregate into cylindrical masses along sections of the twigs. They are found in
woodlands and open forests along watercourses and on the edges of swamps (Craven,
2008).
Figure 2.27: Melaleuca bracteata var. revolution gold (adapted from Osunsanmi et
al., 2015)
2-67
2.15.1 Scientific classification of Melaleuca bracteata
Kingdom:
Plantea
Plant subkingdom: Tracheobionta
Super division:
Spermatophyta
Division:
Magnoliopsida
Class:
Magmoliopsida
Subclass:
Rosidae
Order:
Myrtales
Family:
Myrtaceae
Genus:
Melaleuca L
Species:
Melaleuca bracetata
(Barlow, 1998)
2.15.2 Some other Melaleuca genuses
There are various melaleuca genuses from the family of Myrtaceae. These include;
Melaleuca acuminate
Melaleuca lternifolia
Melaleuca agathosmoides
Melaleuca adnata
Melaleuca acacioides
Melaleuca acerosa
Melaleuca amydra
Melaleuca alsophila
Melaleuca adenostyla
Melaleuca bracteata
2-68
(Aboutabl et al., 1998)
2.15.3 Economic importance of Melaleuca bracteata var. revolution gold
Melaleuca bracteata var. revolution gold (Figure 2.26) is cultivated widely because of its
compact shape and ability to grow in different environmental conditions. The plant is
pest and disease free, and is cultivated mostly in tropical regions of South Africa and
other tropical areas worldwide. In Australia, it is used as a food plant and an ornamental
plant (Craven and Lepschi, 1999).
The leaves of Melaleuca bracetata are commonly used by traditional healers for the
treatment and prevention of diseases; the leaves are chewed to alleviate headache and
other ailments. The flexibility and softness of the stem bark of this plant made it an
important tree for aboriginal people. The stem bark is used as a sleeping mat, food
wrapper, a raincoat, for bandages, and for sealing holes in canoes (Byrnes, 1986).
The wood is hard, heavy and durable, and it could thus be used for poles and posts.
The trees also serve as good shelter and could potentially be used in the control of
erosion (Craven and Lepschi, 1999).
The essential oil from Melaleuca bracteata has been demonstrated to have good
antifungal and antibacterial properties, and eliminates warts and the human papilloma
virus (Cribb and Cribb, 1981; Oliva et al., 2003). The Melaleuca bracteata oil is a major
component in
―
Burn aid
‖
, a commonly used first aid treatment for minor burns. This
Melaleuca bracteata oil is also used in pet fish medications, such as Bettafix and
Melafix (Takarada, 2004). These medications are use for the treatment of fungal and
bacterial infections (Hammer, 2003; Mondello, 2003). The Melaleuca bracetata oil is
also used as a germicidal, insecticidal and as an antiseptic (Yatagai, 1997).
Dostları ilə paylaş: |