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Chapter
Natural Products as Therapeutic
Option for Echinococcossis
Yaw Duah Boakye, Doreen Kwankyewaa Adjei,
Kofi Oduro Yeboah, Daniel Obeng Mensah, Newman Osafo,
Theresah Appiah Agana, Vivian Etsiapa Boamah
and Christian Agyare
Abstract
Until the 1980s surgery remained the only treatment option for cystic
echinococcosis, a neglected tropical disease caused by infection with tapeworms of the
genus Echinocococcus. Following the development of the benzmidazoles, there has
been an increase in the use of chemotherapy over the years, especially as an adjunct to
surgery or in the management of inoperable cysts. In spite of their usefulness, both
surgery and chemotherapy are associated with significant limitations that warrants
the search for or consideration of alternative treatment options such natural products.
This chapter aims to discuss the scolicidal activity of different species of medicinal
plants and their active metabolites in the treatment of echinococcosis. Excerpta
Medica Database, Google Scholar, PubMed Central and Scopus were electronic data-
bases used to retrieve the relevant literature. Medicinal plants used commonly and
effectively against protoscoleces were Zataria multiflora,Nigella sativa,Berberis
vulgaris,Zingiber officinale, and Allium sativum. Only Z. multiflora and A. sativum were
shown to effective against Echinococcus granulosus protoscoleces in vivo. In addition,
these natural products have not been associated with any significant adverse effect. In
animal models Thus, natural products with demonstrated activity against E. granulosus
may serve as alternative therapy in the management of echinococcosis.
Keywords: cystic echinococcosis, natural products, benzmidazoles, medicinal plants,
toxicity
1. Introduction
Helminths are generally classified into two main phyla: Platyhelminthes (cestodes
and trematodes) and Nematodes [1]. A third of the 3 billion people living in low socio-
economic conditions in the developing countries of the Americas, Asia, and sub-
Saharan Africa are infected with one or more helminthes. Helminthic parasitic infec-
tions are regarded as neglected tropical diseases because less than 1% of global
research funding is allocated to these infections or diseases [2].
1
The etiological agent of cystic echinococcosis (CE)/hydatid disease, a neglected
tropical disease with a global prevalence, is the cestode, Echinococcus granulosus sensu
lato (s.l) (E. granulosus), a tapeworm of the family, Taenidae [3]. Globally, 1 to 3.6
million disability-adjusted life years (DALYs) are caused by human CE infections;
with the majority of these cases living in low- and middle-income countries [4]. In
China, South America, Europe, Australia, and Africa, CE raises a serious economic
and public health concern. Moreover, infestations with CE result in great losses to the
livestock industry (about $3 billion every year) through reduced milk supply, lower
fertility, increased mortality, weight loss as well as morbidity and mortality in humans
[1, 5].
Canids, such as dogs, wolves, foxes, and jackals serve as the infection’s primary
hosts in the home environment, with a wide range of other herbivores including
sheep, goats, water buffalo, and cattle serving as intermediate hosts [5, 6]. Through
the consumption of pasture grass contaminated with E. granulosus eggs released by
infected dogs, intermediate hosts also get infected. The cycle is then completed when
definitive hosts consume cysts (metacestodes) found in various organs (such as the
liver, lungs, spleen, and heart) of infected intermediate hosts, notably sheep and
goats. Ingestion of E. granulosus eggs accidentally from contaminated soil, water, and
vegetables results in human infection. Humans are therefore regarded as the “acci-
dental intermediate hosts”. Humans typically develop fluid-filled hydatid cysts in the
liver and lungs, with less frequency occurring in the abdominal cavity, muscle, heart,
bone, and nervous system. Due to risky practices including sharing a home with
unrestrained dogs, having no regulations governing the killing of animals, and living
in unhygienic settings, socio-economic and cultural determinants have a significant
influence in the transfer of illnesses to people [7].
Clinical signs only appear when the cyst puts pressure on the nearby tissues or
organs or when they rupture, even though the infection may go years without
showing any symptoms. Depending on the development and location of the cyst, the
infection might constitute a major health risk to people. Ultrasound and, to a lesser
extent, serology are the primary imaging methods used to diagnose CE [2, 3]. The
size, location, and quantity of hydatid cysts determine the best treatment plan.
Currently, anthelmintics, surgery, and percutaneous aspiration are the only treat-
mentsavailableforCE.Thechemicalmedications used to treat human hydatid cysts
are albendazole and mebendazole. In order to treat the disease, these medications
are frequently used at high doses, which might have negative effects on the liver and
otherorgans[1].
2. Diagnosis of cystic echinococcosis
Currently, diagnosis of CE is mostly performed by means of imaging techniques
comprising magnetic resonance imaging (MRI), ultrasonography, computed tomog-
raphy (CT) scan and/or conventional chest radiography [8]. These methods are
indispensable, enabling the easy establishment of the specific stage of the hydatids
and also the localization. For instance, the WHO Informal Working Group on Echi-
nococcosis (WHO-IWGE) has issued ultrasonography standardized classification of
stage-specific cystic images for the diagnosis and management of CE [9]. Although
either of these imaging techniques are useful, MRI is preferred over CT due to better
visualization of liquid areas within the matrix [10]. Tumors and infectious lesions are,
however, considered for differential diagnosis [8].
2
Echinococcosis - New Perspectives
As confirmatory test, serological analyses are used to support the findings of the
imaging techniques. These tests may also be used as screening or for follow-up mon-
itoring after CE diagnosis [11]. These serological methods are based on the detection
of specific IgG antibodies produced against E. granulosus. Currently, the main immu-
nological methods for the diagnosis of CE and follow-up in patients with the disease
are enzyme-linked immunosorbent assays (ELISAs) and immunoblotting (IB).
ELISAs are used as a screening test whereas IB is employed as a confirmatory test due
to its higher specificity and sensitivity when compared to other assays [11]. Other
serological methods that have been used in the diagnosis of human CE include immu-
nofluorescence assay, indirect hemagglutination assay, immunochromatographic test
and dot immunogold filtration assay. However, these tests are associated with lower
sensitivity and specificity, thus are used less [12].
Given the pitfalls associated with radiological and immunological techniques,
interest in the use of recombinant proteins and synthetic peptides have increased [9].
These molecular diagnosis or DNA-based analysis are very useful in the diagnosis of
CE because they offer a wider and complete diagnostic picture of CE patients [8].
DNA probes for Southern hybridization tests and polymerase chain reactions are very
helpful in confirming diagnosis of CE. Moreover, PCR has high sensitivity and speci-
ficity for the pathogen’s DNA, thus allows for precise determination of infection status
and identification of genus, species, and genotype [12]. As such, PCR is the foremost
molecular analysis in the diagnosis of human CE.
3. Current treatment protocols
Treatment of CE depends on stage of the disease, size and location of the cyst, and
complications that may be associated with the cysts. Currently, four treatment
modalities are employed for the clinical management of CE. These modalities include
surgery, chemotherapy with synthetic drugs and puncture aspiration injection and re-
aspiration [2]. However, for clinically silent and inactive cysts, active surveillance is
the preferred intervention [13]. In this section, we focus on the strengths and limita-
tions associated with current pharmacological and non-pharmacological management
of CE.
3.1 Surgery
Until the 1980s surgery remained the only treatment option for CE [2]. Although
other treatment modalities have been made available over the past few decades,
surgery remains the treatment of choice for most cases of hydatid hepatic cysts [14].
Surgical intervention enables complete eradication of the parasite, treatment or pre-
vention of complications, and avoidance of relapse. According to WHO-IWGE, treat-
ment strategy of the disease must be based on the cyst stage. Accordingly, surgery is
indicated in patients with cysts greater than 10 cm or with stages 2 or 3b CE that is
with daughter cysts. Patients with other cysts that do not satisfy these criteria may
also require immediate surgical treatment. These include infected cysts, superficial
cysts with a higher risk of rupture and cysts communicating with the biliary tree [15].
Owing to its satisfactory outcomes, surgery is considered the preferred treatment
modality for CE patients with large and complicated cysts [16]. Nonetheless, benz-
imidazole must be administered to sterilize cyst content prior to surgical treatment in
order to prevent dissemination or anaphylaxis [14]. In addition, scolicidal solutions
3
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
must be used to eradicate protoscolices of the parasite that may be present within the
content of the cyst. Such scolicidal solutions may include silver nitrate, hypertonic
saline, povidone iodine, hydrogen peroxide and the anthelminthic albendazole which
can be used alone or in combination.
In surgical management of CE, cysts that lie deep, in close proximity to large
vessels, and contain multiple daughter cells or calcified cysts must be treated with
open surgery [14]. In contrast, laparoscopic surgery is indicated for superficial cysts
located on the anterior side of the liver. If open surgery is indicated, the operative site
is scrupulously packed and a variety of conservative and radical operative techniques
are employed [14].
3.1.1 Conservative operations
In conservative surgical procedures used in the management of hydatid cyst,
only the parasitic cyst contents are removed. Pericystic membranes are retained and
procedures such as capitonnage, omentoplasty and external drainage are used to
manage the residual cavity. The modified Aydin technique has also been used in the
management of giant pulmonary hydatid cyst. This technique is advantageous since it
avoids major capitonnage complications [17]. In these conservative procedures, the
cyst is exposed safely and the pericystic area and operating field are covered with
scolicide-soaked pads. Thus, preventing the spillage of parasite-containing contents
into surrounding tissues and peritoneal cavity. Subsequently, the cyst is punctured
and as much fluid as possible is aspirated following which the scolicide is instilled into
the cyst. This is to prevent dilution of the scolicidal agent after introduction into the
cyst [18].
The scolicidal agent is allowed to remain in the cyst cavity for a period of 5–15 min
after which it is aspirated, and the cyst is unroofed. In the case of hepatic hydatid cyst,
cyst contents including germinative membrane and daughter cysts, are evacuated and
the surgeon carefully explores the cavity for any gross communication with the biliary
tract. At the same time, the surgeon explores the presence of any exogenous cyst that
may be embedded in the wall [18]. Following this, external or internal drainage,
capitonnage, omentoplasty, marsupialization, and introflexion can be used to manage
the residual cavity [14]. These may give rise to the Mabit procedure where
omentoplasty and external drainage is used to extract the parasite from the cavity, or
Posadas procedure which employs capitonnage, i.e., the surgical closure of the cyst
cavity via the application of sutures so as to cause approximation of the opposition
surfaces. In all, conservative surgery is easy, safe, and rapid, but has significant
limitations such as high morbidity and recurrence rates that sometimes necessitates
the choice of radical operations [14].
3.1.2 Radical surgery
In recent times, the use of conservative surgical procedures has become more
acceptable among surgeons [19]. However, invasive surgery is sometimes still needed
to eradicate parasitic infection in patients with complicated hepatic cysts and also in
patients who do not respond to anthelmintic therapy [16]. In contrast to conservative
techniques, radical techniques used in hepatic infections can include cystectomy and
may involve removal of the germinative layer by non-anatomical liver resection.
With the aim of eradication or elimination of local relapse or complications due to
false orbiting, radical surgeries remove the cyst along with the pericystic membrane
4
Echinococcosis - New Perspectives
and parasitic contents. The procedure may also involve liver resection if indicated
[14]. In the treatment of hepatic cysts with radical surgery, procedures such as partial
pericystectomy, subadventitial cystectomy, and hepatic resection may be used. Either
procedure is associated with its own advantages and limitations. To illustrate,
subadventitial cystectomy is not suitable for patients with cysts located near vital
vessels of the liver or bile ducts. Hepatic resection on the other hand is time-intensive,
nonetheless associated with a low rate of cyst recurrence. Although, recurrence rate is
lower in subadventitial cystectomy and hepatic resection, the former is associated
with less injury to healthy liver tissue than hepatic resection. In contrast to hepatic
resection, pericystectomy and partial pericystectomy are easy to perform, less time-
invasive and associated with little blood loss [14].
Regardless of the choice of procedure, depending on the cyst location, effective-
ness and safety, radical surgery aims at a common goal, that is, the residual cavity
must always be treated with excellent care [20]. This is crucial in preventing biliary
leakage, biliary fistula, and abscess formation. Radical surgical approaches are associ-
ated with a low risk of postoperative complications, fewer relapse cases, long postop-
erative hospitalization, and low mortality rates; they are all operations with a high
difficulty level mostly suitable for highly specialized liver surgeons. Owing to its low
risk of postoperative complications, relapse and low mortality rates, radical surgery is
considered superior to conservative surgery [21].
In spite of the low morbidity and mortality associated with radical surgeries, these
procedures might not be applicable in all cases [22]. Thus, influencing the introduc-
tion of less harmful and more accurate treatment options such as chemotherapy.
3.2 Chemotherapy
According to the WHO and the World Organization for Animal Health’s Manual
on Echinococcosis in Humans and Animals, chemotherapy is indicated for inoperable
cysts, cysts in multi organs, and for pre-emptive treatment of secondary echinococ-
cosis. In contrast, the use of chemotherapy-alone is contraindicated in early and late
pregnancy, and patients with inactive cysts or cysts with a greater risk of rupturing
[23]. Although, chemotherapy has been indicated for inoperable cysts, evidence from
several studies conducted over the past few decades, mainly case series, suggest that
chemotherapy could be an alternative to surgery in patients with uncomplicated cysts
[13]. This has resulted in an increased use of chemotherapy over the years.
Given the above, various factors need to be considered prior to the choice of
anthelminthic therapy in the treatment of CE. When indicated, patients with inoper-
able cysts must undergo long-term treatment with benzimidazoles such as
albendazole and mebendazole, or the pyrazinoisoquinoline praziquantel [24].
3.2.1 Mebendazole
Mebendazole, chemically known as methyl 5-benzoyl-1H-benzimidazole-2-yl-
carbamate, is a broad spectrum anthelmintic used for the treatment of helminth
infestations in both humans and animals. Since its development in the 1970s,
mebendazole has been useful in the treatment of helminthiasis with varying causative
organisms such as CE, ascariasis, trichuriasis and enterobiasis [25]. Recently, the use
of mebendazole has largely been replaced with albendazole due to some advantages of
the latter. For instance, the poor solubility of mebendazole limits its use in the treat-
ment of CE and other tissue helminthiases. Consequently, the use of mebendazole in
5
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
hydatid cyst is obsolete, with albendazole being more preferred due to its better
intestinal absorption and lower dosage [26].
3.2.2 Albendazole
Albendazole, a benzimidazole carbamic acid methyl ester, is a broad spectrum
anthelmintic used for the treatment of various helminthiases. Since its introduction
about four decades ago, the drug has been used for its vermicidal activity in infectious
conditions such as CE, toxocariasis, taeniasis, gnathostomiasis, and cysticercosis [27].
By binding to intracellular microtubules, albendazole preferentially inhibits parasite’s
tubulin polymerization and prevents assembly of microtubules. Consequently, glu-
cose uptake decreases resulting in the depletion of the parasite’s glycogen stores [28].
This coupled with degenerative changes in the germinal cell mitochondria and endo-
plasmic reticulum, and increased lysosomal activity, albendazole decreases produc-
tion of adenosine triphosphate and induces autolysis. Thus, reduces the survivability
of the parasite.
In spite of its use in the medical treatment of CE, albendazole is also a useful
adjunctive therapy to percutaneous treatment or surgery in preventing secondary CE.
When used as an adjunct, albendazole is initiated at least 4–30 days before surgery,
and continued for at least 1 month after surgery or percutaneous procedure [26].
Notwithstanding the usefulness of albendazole in the management of CE, studies have
reported some adverse effects associated with its use. In one cohort study involving 35
children with abdominal CE, mild increase in the liver enzymes along with mild
leukopenia were observed at daily doses of 10–15 mg/kg for 1 month [29]. Rarely, liver
failure, hemolytic anemia and pancytopenia has been reported [25].
3.2.3 Praziquantel
Praziquantel is a broad spectrum anthelmintic that has been in use since 1980. The
drug exhibits activity against various helminthic infections of human and veterinary
origin. Although the exact mode of vermicidal action is uncertain, praziquantel is
believed to cause rapid paralytic muscular contractions by increasing intracellular
calcium influx and tegumental disruption. This paralytic action of the drug expels the
worms from their primary habitat, after which they undergo degeneration due to
tegumental disruption [30].
Although useful in the treatment of CE, praziquantel is not indicated as first-line
option. The drug is nonetheless effective in perioperative treatment and in the treat-
ment of bone or disseminated CE [31]. For instance, when used together with
albendazole, praziquantel is effective in the preoperative treatment of intra-
abdominal hydatidosis [26]. Unlike albendazole, the use of praziquantel is safe in
pregnancy.
3.3 Challenges with current treatment protocols
Given the above, current surgical and chemotherapeutic interventions are essential
therapeutic tools in the management of CE. However, these treatment strategies may
be associated with some challenges that may limit their usefulness in the treatment of
CE. For instance, surgical treatment of hepatic hydatid cysts may result in major
complications such as cholestatic jaundice. Rupturing of cyst into the biliary tree
adjacent structures, or the peritoneum during surgery may also result in secondary
6
Echinococcosis - New Perspectives
infection, sepsis and anaphylaxis [14]. Postoperative hemorrhage, incisional fistulae,
cholangitis, surgical site infection, pneumonia and pulmonary embolism are all major
complications that have been reportedly observed following surgery. Moreover, spill-
age of cyst contents during removal and incomplete removal of the endocyst increases
the risk of recurrence of the disease. The risk of local and secondary disease recurrence
may also be increased by exophytic cyst development that surgeons fail to notice
during surgical interventions [32].
Similarly, the use of benzimidazoles is also associated with significant drawbacks,
albeit improves life-expectancy in patients with CE [24]. Specifically, the use of
current chemotherapeutic agents can reduce cyst size but months of therapy may be
required [23]. This may be explained in part by the poor oral absorption and the
reduced oral bioavailability of these drugs. As a result, recent studies have suggested
developing new formulations such as nanocrystals and liposome formulations to
enhance oral absorption and bioavailability, and reduce duration of therapy [33, 34].
Not only is chemotherapy limited by its long course in the treatment of CE, but this
treatment approach is also not effective against all stages of cyst development. Benz-
imidazoles may get diluted in large cysts with size greater than 10 cm, hence less
effective against such large cysts. In addition, treatment failure and disease recurrence
are more common when chemotherapeutic agents are used in treatment of CE
involving multiple, or complicated cysts surrounded by thickened calcified tissue
layers [10, 35].
Albeit the relevance of current treatment protocols cannot be overstated, these
treatment approaches are associated with significant limitations that warrants the
search for or consideration of alternative treatment options. These alternative options
include natural products such as monoterpenes, taxanes, isoflavonoids and plant
extracts which have been shown to be effective in the management of CE.
4. Natural products with reported activity against Echinococcus
For contemporary systems of herbal and natural drug development, medicinal
plants with dependable therapeutic effects are valuable. The synthesis of more com-
plicated semisynthetic chemical compounds can start with bioactive substances found
in plants, which can also be used as a direct source of medicinal or bioactive chemicals
[2]. Finally, plants can be utilized as bioactive markers for spectroscopic and chro-
matographic investigations together with the discovery of new compounds [36]. Iso-
lated chemicals of medicinal plants can lead to the development of new medications.
In this chapter, we discuss the medicinal plants, fungi, and isolated chemical com-
pounds shown to have scolicidal activity against the protoscoleces of E. granulosus.
4.1 Medicinal plants with reported activity against Echinococcus
In all, 57 species were found to have been employed as echinococcicidal agents in
the in vitro investigations as a result of our comprehensive review. The most popular
extract for killing protoscoleces was Zataria multiflora, which was then followed by
Nigella sativa,Berberis vulgaris,Zingiber officinale, and Allium sativum (Table 1).
The in vitro research made considerable use of leaves among herbs, methanolic
extract among extraction, and herbs among plant forms. In the in vitro trials, it was
discovered that plants like Z. multiflora,Ferula assafoetida, and B. vulgaris had a better
efficiency. At a dosage of 1 mg/mL, Z. multiflora eliminated all scoleces in 5 min. At
7
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
Botanical name Extraction
method
Part used Phytochemical component Concentration
(mg/mL)
Exposure
time
(min)
Scolicidal
efficacy
(%)
References
Allium noeanum (Reut) Ethanolic Leaves Flavonoid 0.49 0.5 100 [37]
Allium Sativum (Garlic) Ethanolic/
chloroform
Garlic
cloves
Silver nitrate 200 15 17 [38]
Allium sativum (Garlic) Methanolic Garlic
cloves
Mannitol 50 10 100 [39]
A. sativum (Garlic) Chloroform
extraction
Fresh garlic N/A 200 1 100 [40]
Artemisia (Wormwood) Methanolic NA N/A 100 15 97.24 [41]
Artemisia sieberi
(Wormwood)
Hydrodistillation Aerial parts α-Thujone (31.5%) 0.005 120 99.30 [42]
Artemisia sieberi
(Wormwood)
Aqueous As a whole N/A 50 20 100 [43]
Atriplex halimus
(Orache)
Aqueous Leaves Phenolic and flavonoids 60 120 99.36 [44]
Berberis vulgaris
(Barberry)
Aqueous Fruit N/A 4 30 100 [45]
B. vulgaris (Barberry) Methanolic Root Berberine 2 10 100 [46]
Blepharocalyx salicifolius
(Kunth)
Aqueous Leaves Gallic acid and rutin 200 5 100 [47]
Bunium persicum (Black
Caraway)
Hydrodistillation Seeds g-terpinene (46.1%), cuminaldehyde (15.5%), r-cymene
(6.7%), and limonene (5.9%)
0.0125 10 100 [48]
Cannabis sativa (Hemp) N/A Aerial parts N/A 0.01 10 26.08 [49]
Capparis Spinosa
(Caper)
Methanolic Fruit Flavonoids, tannins, terpenoids, glycosides and alkaloids 300 20 100 [50]
Cassia fistula (Golden
shower)
Ethanolic Fruits N/A 100 60 67.74 [51]
8
Echinococcosis - New Perspectives
Botanical name Extraction
method
Part used Phytochemical component Concentration
(mg/mL)
Exposure
time
(min)
Scolicidal
efficacy
(%)
References
Cinnamomum
zeylanicum (Cinnamon)
Hydrodistillation Bark Cinnamaldehyde (91.8%), metoxicinamate (1.57%), and
_ pinene (1.25%)
0.05 5 100 [52]
Coriandrum sativum
(Coriander)
Hydrochloric
acid + diethyl
ether
Seeds Phenols 750 10,080 100 [53]
Corylus spp. Hydro-alcoholic Seeds N/A 50 20 98 [54]
Cucurbita moschata
(Pumpkin)
Hydroalcoholic Seeds N/A 1 60 16 [55]
Curcuma longa
(Turmeric)
Ethanolic As a whole N/A 30 30 100 [56]
Curcuma longa
(Turmeric)
Hydrodistillation Rhizome α-turmerone (27.1%), β-turmerone (21.8%), l-
phellandrene (8.8%), and ρ-cymene (5.4%)
0.1 5 100 [57]
Curcuma zadoaria
(White turmeric)
Hydrodistillation Rhizome Pentadecane (29.6%), Delta-3-carene (14.7%), and Cis-
cinnamic Acid (8.4%)
0.15 7 100 [58]
Eucalyptus globules
(Bluegum)
Aqueous Leaf Eucalyptol (79.32%) 10 5760 94 [59]
Eucalyptus globulus
(Bluegum)
NA Leaves Eucalyptol (79.32%) 5 3 100 [59]
Ferula macrecolea
(Koma)
Hydrodistillation Leaves Terpinolene (77.72%), n-nonanal (4.47%), and linalool
(4.35%)
0.3 10 100 [60]
Lepidium sativum
(Garden cress)
Aqueous Leaves N/A 100 15 100
Mallotus philippinensis
(Kamala Tree)
Methanolic Fruit N/A 20 120 100 [61]
Melaleuca alternifolia
(Tea tree)
N/A Tree oil Terpinen-4-ol (35.4%), _-terpinene (11%), -terpinene
(20.4%) and 1,8-cineole (3.4%)
20 5 90 [62]
9
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
Botanical name Extraction
method
Part used Phytochemical component Concentration
(mg/mL)
Exposure
time
(min)
Scolicidal
efficacy
(%)
References
Mentha species
(Lamiaceae)
Methanolic Aerial parts Phenolic, flavonoid and flavonol 200 10 99.54 [62]
Myrtus communis (True
myrtle)
Hydrodistillation Leaves α-pinene (24.7%), 1,8-cineole (19.6%), and linalool
(12.6%)
0.1 5 100 [63]
Myrtus communis (true
myrtle)
Methanolic Leaves N/A 100 20 100 [64]
Nectaroscordum tripedale
(Sicilian Honey Garlic)
Ethanolic Leaves Terpenoids, flavonoids, tannins and fatty acids 50 10 100 [1]
Nigella sativa (Black
Cumin)
Hydrodistillation Seeds Thymoquinone 10 10 100 [1]
Nigella sativa (Black
Cumin)
Methanolic Seeds Thymoquinone 50 30 100 [1]
Ocimum bacilicum
(Sweet basil)
Methanolic Leaves N/A 100 60 24.10 [65]
Olea europaea (Olive) Aqueous Leaves N/A 1 120 96.7 [66]
Olea europaea (Olive) Ethanolic Leaves N/A 150 25 100 [1]
Peganum harmala
(Syrian rue)
Ethanolic Seeds N/A 62.5 2880 100 [67]
Pelargonium roseum Hydrodistillation Leaves N/A 0.05 60 100 [68]
Pestalotiopsis spp. Methanolic Leaves,
stems and
roots
N/A 30 30 92 [1]
Piper longum (Long
pepper)
Methanolic Fruits Phenolics, flavonoids, alkaloids, tannins, terpenoids, and
glycoside
100 60 100 [1]
Pistacia khinjuk
(Khiniuk)
Methanolic Fruits Terpenoids, flavonoids, and tannins 100 10 100 [1]
10
Echinococcosis - New Perspectives
Botanical name Extraction
method
Part used Phytochemical component Concentration
(mg/mL)
Exposure
time
(min)
Scolicidal
efficacy
(%)
References
Poikilacanthus
glandulosus (Ariza)
Ethanolic Branches Polyphenols and flavonoids 0.01 15 100 [68]
Punica granatum
(Pomegranate)
Alcoholic Stem and
root
N/A 9 1440 100 [1]
Rhus coriaria (Sumac) Methanolic As a whole N/A 30 20 98.89 [69]
Ruta graveolens (rue) Methanolic Aerial parts Phenolic (25.53%), flavonoids (6.6%) and tannins (8.0%) 40 720 100 [1]
Salvadora persica
(Miswak)
Ethanolic Root Indole alkaloids, flavonoids, tropaedoin, triterpenes,
phytosterols, and isothiocyanates
50 10 100 [1]
Satureja hortensis
(summer savory)
Aqueous Aerial parts Carvacrol and -terpinene 1 20 100 [70]
Satureja khuzistanica
(Jamzad)
Hydrodistillation Leaves and
flowers
Carvacrol 5 60 100 [71]
Saussurea costus (Costus) Ethanolic Root N/A 250 60 100 [1]
Sideritis perfoliate
(Ironwort) 25 60,100
Methanolic Leaves and
flowers
Fumaric acid (260.13 mg/L), syringic acid (27.92 mg/L)
and caffeic acid (26.84 mg/L), and a flavonoid, luteolin
(11.23 mg/L)
25 60 100 [1]
Silybum marianum
(Milk thistle)
Ethanolic Seeds Silydianin (14.41%), isosilybin A (10.50%), and
silychristin (10.46%)
0.5 60 77 [1]
Taxus baccata (Common
yew)
Hydroalcoholic As a whole Octane (13.36%), 4-methoxycarbonyl
3,5-diphenyl-1 (8.30%), and
9,12,15-octadecatrienoicacid (10.75%)
150 60 66.60 [72]
Teucrium polium (Felty
germander)
Ethanolic Flowers N/A 100 50 100 [1]
Thymus vulgaris (Garden
thyme)
Hydrodistillation Leaves Thymol 0.5 103,680 100 [73]
11
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
Botanical name Extraction
method
Part used Phytochemical component Concentration
(mg/mL)
Exposure
time
(min)
Scolicidal
efficacy
(%)
References
Trachyspermum ammi
(Ajowan)
Hydrodistillation Fruits Thymol 5 10 100 [74]
Zataria multiflora
(Shirazi thyme)
Methanolic Leaves Carvacrol and thymol 25 1 100 [1]
Zataria multiflora
(Shirazi thyme)
Diethyl ether Essential oil Thymol (66.9%), carvacrol (15.2%), carvone (7.3%),
neo-dihydrocarveol (2%), and 1,8-Cineole (1.6%)
1 5 100 [1]
Zataria multiflora
(Shirazi thyme)
Methanolic Leaves Carvacrol and thymol 10 10 100 [75]
Zataria multiflora
(Shirazi thyme)
Hydrodistillation Aerial parts Thymol (41.8%), carvacrol (28.8%), and p-cymene
(8.4%)
0.1 10 100 [1]
Zataria spp. (Satar) Hydrodistillation Leaves Carvacrol and thymol 100 1 100 [1]
Zingiber officinale
(Ginger)
Methanolic Rhizome N/A 100 30 100 [1]
Zingiber officinale
(Ginger)
Methanolic Root N/A 100 40 100 [1]
Zingiber officinale
(Ginger)
Aqueous As a whole [6]-gingerol 100 1440 100 [76]
Zingiber officinale
(Ginger)
Ethanolic Rhizomes
sheets
N/A 200 30 100 [1]
Ziziphora tenuior (Mint) Ethanolic Shoots Thymol 100 240 40.25 [77]
Table 1.
List of medicinal plants with in vitro activity against protoscoleces of Echinococcus.
12
Echinococcosis - New Perspectives
dosages of 60 g/mL and 2 mg/mL for 10 min, F. asafoetida and B. vulgaris were shown
to have 100% effectiveness [1, 2].
Two plant species, Z. multiflora and A. sativum, showed in vivo anti-echinococcal
activity. In the in vivo studies for their validation against E. granulosus protoscoleces,
the leaf extracts, peels and other parts were tested (Table 2) [1].
4.2 Fungi with reported activity against Echinococcus
Characteristic ultrastructural changes were observed when protoscoleces of E.
granulosus was treated with extract of endophytic fungi Eupenicillium and
Pestalotiopsis sp. isolated from Azadirachta indica and Chaetomium sp. Piper longum
plants respectively. Pestalotiopsis sp. showed a promising scolicidal activity up to 97%
mortality just within 30min of incubation. In a study comparing commercial chitosan
to fungal chitosan isolated from Penicillium waksmanii and Penicillium citrinum, it was
observed that Fungal chitosan was the most bioactive type with higher degree of
deacetylation showed stronger scolicidal activity in vitro [88].
4.3 Isolated compounds from natural products with reported activity against
E. granulosus
A total of 8 active chemicals compounds extracted from various medicinal plant
are reported to show activity against E. granulosus. They are, thymol, carvacrol, men-
thol, berberine, genistein, thymoquinone, ampelopsin, and gallic acid (Figure 1). In
an in vitro study, thymol, berberine, and thymoquinone showed substantial in vitro
scolicidal action at concentrations of 0.1, 0.5, and 1 mg/ml after exposure for 5, 10,
and 1 min. In vivo tests with thymol and carvacrol also showed promising scolicidal
efficacy [89, 90].
5. Toxicity and safety profile of the natural products with reported
activity against E. granulosus
With increased advocacy for the use of natural products in the management of
conditions such CE comes the heightened interest in the safety of these natural
products. Obviously, alternatives to synthetic protoscolicidal agents are being sought
not only because of associated reduced efficacy, increased recurrence rates and
increased drug resistance, but also to the incidence of adverse effects [10]. Thus,
successful integration of natural products in the treatment of CE will require the
establishment of the toxic profile of these natural products. It is to be noted that, the
idea that ‘natural product’always implies ‘safe’is deceptive since these products
contain pharmacologically active compounds which may exert detrimental effects at
high doses or in specific conditions [91].
Given the above, toxicity assessments have been conducted on some plants and
active metabolites with reported activity against E. granulosus. For instance, Z.
multiflora was associated with no significant toxicity in mice [92]. Similarly, essential
oil obtained from C. longa was not shown in toxicological studies to exert any signif-
icant toxicity in NIH mice [93]. In vivo toxicity assessments of thymol in mice and
golden hamsters also showed no overt toxicity or changes in serum biomarkers such as
uric acid and bilirubin [94, 95]. Similarly, berberine at the tested clinical doses was not
identified to exert cytotoxic and mutagenic effects [96]. Thymoquinone when
13
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
Botanical name
(common name)
Extraction
method
Part used Phytochemical component Experimental
animal
Concentration
(mg/mL)
Exposure
time (min)
Scolicidal
efficacy
(%)
Ref
Algerian propolis
(Propolis)
Ethanolic N/A Polyphenol, flavonoid Mice 25 10 100 [1]
Allium sativum
(Garlic)
Methanolic N/A N/A Mice 50 10 100 [78]
A. sativum
(Garlic) Mice
Methanolic Garlic
cloves
1% Alliin Mice 80 43,200 Significant [79]
Annona squamosa
(Sugar apple)
Alcoholic Leaves N/A Rats 100 2880 100 [1]
Artemisia Herba-
alba
(Wormwood)
Ethanolic Leaves
and
flowers
Alkaloids, phenols Mice 0.28 1440 55.17 [1]
Nigella sativa
(Black cumin)
Ionotropic
gelation
technique
Seed N/A Mice 1.14 86,400 100 [1]
Pistacia vera
(Pistachio)
Hydrodistillation Branch Essential oil Mice 200 10 100 [80]
Punica granatum
(Pomegranate)
Aqueous Peels N/A Mice 16 2880 100 [81]
P. granatum
(Pomegranate)
Aqueous N/A Peel Mice 0.65 86,400 66.7 [82]
Sophora
moorcroftiana
N/A seeds N/A Mice 0.25 60,480 76.1 [83]
Zataria multiflora Essential oil and
oleic acid
Essential
oil
N/A Mice 20 10 100 [84]
Zataria multiflora
(Shirazi thyme)
Diethyl ether Aerial
parts
Gallic acid (1.1618 mg/g), catechin (2.808 mg/g),
caffeic acid (5.531 mg/g), and quercetin (9.961 mg/g)
Mice 0.04 43,200 Significant [85]
14
Echinococcosis - New Perspectives
Botanical name
(common name)
Extraction
method
Part used Phytochemical component Experimental
animal
Concentration
(mg/mL)
Exposure
time (min)
Scolicidal
efficacy
(%)
Ref
Zataria multiflora
(Shirazi thyme)
Methanolic Leaves Thymol (66.9%), carvacrol (15.2%), and carvone
(7.3%)
Mice 8 43,200 100 [86]
Zataria multiflora
(Shirazi thyme)
Hydrodistillation Essential
oil
Thymol Mice 2 10 100 [87]
Zingiber officinale
(Ginger)
Ethanolic As a
whole
N/A Mice 150 60 100 [1]
Table 2.
List of medicinal plants with in vivo activity against protoscoleces of Echinococcus granulosus.
15
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
assessed for mortality and toxicity in mice, at doses of 0.1, 0.2, 0.3 mg/ml for a period
of 3 months was proved to be safe [97].
Albeit toxicity data may not be available on all medicinal plants shown to be
effective against E. granulosus, available evidence on numerous other plants shows
that these natural products may be safely used in the treatment of CE [98, 99].
6. Discussion
Medicinal plants with dependable therapeutic effects are valuable sources of bio-
active substances that can be developed into potential lead compounds in the devel-
opment of drugs for treatment of CE, a neglected tropical disease [2]. Due to the rise
in the emergence of resistant species associated with infectious diseases, developing
novel and effective drugs is imperative for the continuous survival of the human race.
Owing to this, there has been resurgence in the search of natural products that can
serve as alternative synthetic agents in the management of diseases. These natural
products contain a large variety of secondary metabolites that possess several biolog-
ical effects including anthelminthic activity [100]. As such, large numbers of natural
products have been screened particularly against E. granulosus protoscolices with the
hope of identifying natural products with prominent scolicidal potential.
One such natural agent with prominent scolicidal activity is Zataria multiflora, the
most reputable member of the family Lamiaceae [100]. It has been shown that, the
essential oils of Z. multiflora exert powerful anti-hydatid effect even with short expo-
sure times [101]. This remarkable activity of Z. multiflora essential oils has been
Figure 1.
Active chemicals compounds extracted from various medicinal plant are reported to be active against
Echinococcus granulosus. a: thymol; b: menthol; c: carvacrol; d: berberine.
16
Echinococcosis - New Perspectives
attributed to the presence of significant phenolic monoterpenes which contains a
hydroxyl group and possess an innate hydrophobic nature. The presence of a hydroxyl
group and the hydrophobic nature of phenolic compounds enable Z. multiflora essen-
tial oils to penetrate cell membranes resulting in the death of the helminth [102].
In eukaryotic cells, phenolic monoterpenoids primarily decrease the integrity of
plasma and mitochondrial membranes, resulting in cell death. However, the exact
mechanism of action of phenolic monoterpenes in protoscoleces has yet to be deter-
mined, albeit it has been shown to penetrate the cell membrane, damage the lipid
bilayer and, alter cell permeability. This results in leakage of intracellular components,
which lowers the membrane electric potential. This change in the plasma membrane
electric potential probably causes leakage of ATP, proteins, potassium and calcium,
resulting in membrane damage and cell death [103].
Other natural products such as the medicinal plants Ferula assafoetida and A.
sativum, fungal chitosan, and extracts of endophytic fungi Eupenicillium and
Pestalotiopsis sp. isolated from Azadirachta indica and Piper longum, respectively have
also shown significant scolicidal activity. Essential oils obtained from Ferula
assafoetida contain disulfide compounds which have been shown to be responsible for
their scolicidal action [104].
In vitro and in vivo tests have both been used in investigating the pharmacokinetic
characteristics and pharmacodynamic effects of target extracts, as well as host
immune reaction to these natural products. However, majority of studies that evalu-
ated the protoscolicidal activity of different medicinal plants during the past two
decades have utilized in vitro assays. Only a few studies involved in vivo animal models
[1]. More in vivo screening of these natural products with effect against CE are needed
to develop a complete picture of their efficacy and toxicity in whole organisms.
Considering currently available protoscolicidal agents are associated with serious
adverse effects, close attention must be paid to the toxicity of these natural products
in other to identify suitable alternatives to current management [10]. A good
protoscolicidal agent is one that is steady in the cystic contents and possesses the least
toxicity [105].
Moreover, owing to the multiplicity of active metabolites found in natural prod-
ucts, the risk of development of drug resistance may also be low. Data from toxicity
studies available on these medicinal plants also shows the reduced risk of adverse
effects associated with their use. However, additional studies will be desired to prove
these outcomes by establishing the toxicity profile for all the other species of plants
identified to possess activity against E. granulosus. In addition, the exact mechanism
by which the extracts and their isolated compounds exert scolicidal activity, and their
pharmacokinetic profiles must be well established. Knowledge obtained from these
suggested studies should be well synthesized and used to appropriately design ran-
domized controlled trials in human subjects in order to bridge the gap between the
bench and the bedside for CE treatment.
7. Conclusion
Cystic echinococcosis is a public health menace, affecting humans and livestock
worldwide. Although drug treatment is available for its management, in many cases,
existing drugs are insufficiently efficacious, ineffective due to resistance, relative
toxic or contraindicated in some populations. Thus, hindering global efforts to elimi-
nate this neglected tropical disease. Interestingly, natural products have demonstrated
17
Natural Products as Therapeutic Option for Echinococcossis
DOI: http://dx.doi.org/10.5772/intechopen.109614
significant activity against E. granulosus, indicating their potential for use in the
treatment of CE. Medicinal plants such as Zataria multiflora and Allium sativum have
been shown to be effective in both in vitro and in vivo models. In light of the slow
development of new anthelminthics over the past few decades due to lack of com-
mercial attractiveness, natural products may serve as alternatives or adjuncts to cur-
rent treatment approaches. Also, these medicinal plants are rich pools of active
metabolites that may serve as drug leads in the development of scolicidal drugs.
Conflict of interest
The authors declare no conflict of interest.”or delete this entire section.
Author details
Yaw Duah Boakye
1
, Doreen Kwankyewaa Adjei
1
, Kofi Oduro Yeboah
2
,
Daniel Obeng Mensah
3
, Newman Osafo
2
, Theresah Appiah Agana
1
,
Vivian Etsiapa Boamah
1
and Christian Agyare
1
*
1 Faculty of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutics,
Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
2 Faculty of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology,
Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
3 Department of Pharmaceutical Microbiology, School of Pharmacy and
Pharmaceutical Sciences, University of Cape Coast, Cape Coast, Ghana
*Address all correspondence to: cagyare.pharm@knust.edu.gh
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
18
Echinococcosis - New Perspectives
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