Acta Tropica 176 (2017) 179–187

Contents lists available at ScienceDirect

Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Schistosomiasis: Drugs used and treatment strategies MARK

a a a
Lidiany da Paixão Siqueira , Danilo Augusto Ferreira Fontes , Cindy Siqueira Britto Aguilera ,
Taysa Renata Ribeiro Timóteoa, Matheus Alves Ângelosa, Laysa Creusa Paes Barreto Barros Silvaa,
Camila Gomes de Meloa, Larissa Araújo Rolimb, Rosali Maria Ferreira da Silvaa,
⁎
Pedro José Rolim Netoa,
a
Laboratório de Tecnologia dos Medicamentos, Universidade Federal de Pernambuco, Avenida Professor Artur de Sá, CEP 50740-521, Recife, Pernambuco, Brazil
b
Central de Análise de Fármacos, Medicamentos e Alimentos da Universidade Federal do Vale do São Francisco, Avenida José de Sá Maniçoba, CEP 56304-917, Petrolina,
Pernambuco, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Neglected tropical diseases (NTDs) affect millions of people in different geographic regions, especially the
Neglected tropical diseases poorest and most vulnerable. Currently NTDs are prevalent in 149 countries, seventeen of these neglected
Schistosomicides tropical parasitic diseases are classified as endemic. One of the most important of these diseases is schistoso-
Treatment miasis, also known as bilharzia, a disease caused by the genus Schistosoma. It presents several species, such as
Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni, the latter being responsible for
parasitosis in Brazil. Contamination occurs through exposure to contaminated water in the endemic region. This
parasitosis is characterized by being initially asymptomatic, but it is able to evolve into more severe clinical
forms, potentially causing death. Globally, more than 200 million people are infected with one of three
Schistosome species, including an estimated 40 million women of reproductive age. In Brazil, about 12 million
children require preventive chemotherapy with anthelmintic. However, according to the World Health
Organization (WHO), only about 15% of the at-risk children receive regular treatment. The lack of investment by
the pharmaceutical industry for the development and/or improvement of new pharmaceutical forms, mainly
aimed at the pediatric public, is a great challenge. Currently, the main forms of treatment used for schistoso-
miasis are praziquantel (PZQ) and oxaminiquine (OXA). PZQ is the drug of choice because it presents as a high-
spectrum anthelmintic, used in the treatment of all known species of schistosomiasis and some species of ces-
todes and trematodes. OXA, however, is not active against the three Schistosome species. This work presents a
literature review regarding schistosomiasis. It addresses points such as available treatments, the role of the
pharmaceutical industry against neglected diseases, and perspectives for treatment.

1. Introduction affect the population: dengue, Chagas disease, schistosomiasis, leprosy,

Neglected tropical diseases (NTDs) are diseases that primarily affect
the world's poorest and most vulnerable populations. Currently they are
prevalent in 149 countries, affecting 41.4 billion people, causing ap-
proximately 35,000 deaths per day worldwide (Cohen et al., 2016; Sah
et al., 2015; Tlamçami and Er-Rami, 2014). These diseases are caused
by infectious and parasitic agents that affect billions of people per year.
NTDs are, in fact, “neglected” due to under-financing and low re-
cognition by the pharmaceutical industries, although they represent a
serious threat to health in poorly developed countries and are an ob-
stacle to economic development (Brasil, 2010; Santos et al., 2012).
The World Health Organization (WHO) lists 17 neglected tropical
infectious parasitic diseases that are endemic, among the ones that most
leishmaniosis, malaria, and tuberculosis (WHO, 2010). As the affected
populations are mostly low-income people, the interest of the phar-
maceutical industry in advancing therapies for these diseases is scarce,
since it has a low potential for profitable return, even though there is
investment for research related to these diseases (Santos et al., 2012).
Among the most important NTDs is schistosomiasis, also known as
bilharzia. This disease is caused by the Schistosoma genus, which pre-
sents several species, such as Schistosoma haematobium, Schistosoma ja-
ponicum and Schistosoma mansoni, the latter being responsible for
parasitosis in Brazil. In addition, the parasitosis is characterized as
being asymptomatic, but may evolve into more severe clinical forms,
and may even cause death (Sah et al., 2015; Steinmann et al., 2006;
Weerakoon et al., 2015). This helminthiasis is highly prevalent in

⁎
Corresponding author.
E-mail address: rolim.pedro@gmail.com (P.J.R. Neto).

http://dx.doi.org/10.1016/j.actatropica.2017.08.002
Received 12 June 2017; Received in revised form 29 July 2017; Accepted 2 August 2017
Available online 10 August 2017
0001-706X/ © 2017 Published by Elsevier B.V.
L.d.P. Siqueira et al.
subtropical regions of Africa, the Americas, and Asia (Cavalcanti et al.,
2013.)
Neglected tropical diseases have become a public health problem
due to the high morbidity rate worldwide. In many endemic areas,
WHO recommends preventive chemotherapy or large-scale drug ad-
ministration for the control of schistosomiasis, combined with access to
safe drinking water, basic sanitation, hygiene education and control of
snails, an intermediary host (WHO, 2012).
Praziquantel (PZQ), the first anthelmintic to meet WHO require-
ments, is the main drug used to treat schistosomiasis, being effective
and well tolerated by the affected population and reducing parasitic
load and severity of symptoms (Thetiot-Laurent et al., 2013; Gonnert
and Andrews, 1977). Due to its importance in the fight against the
disease, studies have focused on improving some of the specific prop-
erties, such as increasing solubility, or the search for new drug delivery
systems (Arruá et al., 2015; Frezza et al., 2015; Frezza et al., 2013;
Oliveira et al., 2016). In general, these actions aim to circumvent
parasitic resistance, rapid uptake into the bloodstream after ingestion,
and extensive first-pass metabolism (Arruá et al., 2015; Oliveira et al.,
2016).
2. Neglected tropical diseases
NTDs are diseases found mainly, but not exclusively, in areas of
poverty and are responsible for the morbidity and/or mortality of
millions of people per year, comprising a set of 17 diseases (Cohen
et al., 2014; Dias et al., 2013; Fenwick, 2012; Noden and Colf 2013;
Rocha, 2012; Santos et al., 2012; Werneck et. al., 2011). One char-
acteristic of NTDs is the chronicity and incapacitation of the affected
individual; they may also lead to a deformation of the affected limb
(Hortez and Brown, 2009).
Most of the neglected diseases are transmitted to humans through
animals, which act as reservoirs for the pathogens and contribute to the
spread of the diseases (Hortez and Fujiwara, 2014; Noden et al., 2013;
Rocha, 2012; Werneck et al., 2011). Prevention and control of parasitic
diseases require knowledge of the ecological phenomena involving
man, the parasite, and the intermediary hosts or vectors of these
parasites (Santos, 2011).
Over 200 million people are infected with one of the three
Schistosoma species globally, including an estimated 40 million women
at reproductive age (Olveda et al., 2016; Sah et al., 2015). These dis-
eases cause great debilitation in infected people, especially children, as
is the case of schistosomiasis and hookworm, which cause malnutrition,
suppression of growth and cognitive deficits. In pregnant women, these
infections can cause premature delivery, low birth weight, and in-
creased maternal morbidity and mortality. In adults, it may cause dis-
figurement of limbs, such as lymphatic filariasis or blindness, due to
trachoma and onchocerciasis (Hortez and Brown, 2009).
Among the NTDs, malaria affects approximately 17 million people,
intestinal helminthiasis is present in 8 million children, dengue fever in
4–5 million people and more than 800 thousand people contract
Chagas’ disease (Caplan and Zink, 2014; Hortez et al., 2014; Kyelem
et al., 2015).
In Latin America and the Caribbean there are approximately 48
million people living below the poverty line, that is, under $1.25 a day,
while 99 million people live on less than $2 a day (Caplan et al., 2014;
Hortez and Fujiwara, 2014). In this region, there are seven countries
with a human development index (HDI) below 100 and with poverty
levels equivalent to many African countries: four are in Central America
(Guatemala, Nicaragua, Honduras and El Salvador). In Brazil, poverty is
mainly concentrated in the northeastern part of the country, including
the states of Alagoas, Bahia, Ceará, Maranhão, Paraíba, Pernambuco,
Piauí, Rio Grande do Norte and Sergipe (Hortez et al., 2014).
NTDs, such as ascariasis, hookworm infection and the trichuris in-
fection, together with schistosomiasis (caused by Schistosoma mansoni)
are among the most prevalent in Brazil. About 12 million Brazilian
180
Acta Tropica 176 (2017) 179–187
children require preventive chemotherapy with albendazole or me-
bendazole. However, according to WHO, in Brazil, only approximately
15% of children at risk receive regular deworming. Although a national
schistosomiasis control program has been in place since 1975, which
includes drug administration, WHO estimates that less than 3% of the
almost 1.5 million Brazilians infected with S. mansoni are receiving
adequate treatment with Praziquantel or Oxamniquine (Hortez et al.,
2014).
Brazil is considered the largest and most populous country in Latin
America and has the highest burden of neglected tropical diseases, in
terms of individuals requiring pharmacotherapy (Gabrielli et al., 2013).
In Brazil, the populations most affected by NTD are located in the
suburbs of large cities and in rural areas, where there is a greater index
of underdevelopment. The lack of broad coverage of health services and
the small control over natural resources serve as a dissemination factor
for NTDs (Rocha, 2012).
A monitoring system through a specific surveillance should not only
present as the purpose of its program the discovery, investigation and
interruption of continuous transmission, but it should also include the
prevention of infection. An effective surveillance system enables pro-
gram managers to identify areas of risk, affected population groups, as
well as trends for infections in humans and animals requiring inter-
vention and control measures when necessary. As an example, strict
monitoring of Schistosoma in Japan has not been discontinued, since
infected intermediary hosts remained long after the disease in humans
was declared eliminated in the country in 1996 (Bergquist et al., 2015).
The application of molluscicides could be a strategy for the chemical
control of slugs and snails. This is based on the use of metaldehyde and
methiocarb in tablet, granular, and liquid formulations. Metaldehyde
baits are toxic after ingestion, leading to dehydration and subsequent
death of organisms. Similar to carbamate, methiocarb acts on the cen-
tral nervous system, inhibiting acetylcholinesterase, causing the death
of the animal (Cardoso et al., 2015).
2.1. Schistosomosis
Schistosomiasis, also known as a bilharzia, is a disease caused by
Schistosoma trematode, and S. mansoni is responsible for the para-
sitosis in Brazil (Malhado et al., 2016; Santos, 2011; Webster et al.,
2013). This pathology occupies the third position among the main
tropical diseases after malaria and intestinal helminthiases, caused
mainly by three main species of Shistosomas that are capable of in-
fecting man. These are: S. mansoni and S. japonicum, which reside in the
portal system of the liver and mesenteric arteries, and S. haematobium,
which inhabits vessels of the bladder and/or genital tract (Lee et al.,
2014; Sah et al., 2015).
Current estimates from the Global Burden of Disease Study 2010
suggest that 252 million people are infected with schistosomes, 90% of
whom live in sub-Saharan Africa. WHO reports that by 2014, at least
258 million people worldwide required regular and frequent preventive
treatment for schistosomiasis. Recently, however, the disease has ap-
peared in Europe on the French island of Corsica (Merrifield et al.,
2016).
This parasite originated in the basins of two important rivers: the
Nile and Yangtze (Novaes et al., 1999; Webster et al., 2013). Eggs of the
genus Schistosoma, the etiological agent of schistosomiasis, have been
found in the viscera of Egyptian mummies. This helminth spread
through the African continent and it was brought to the Americas
through the slave trade. However, only S. mansoni was thrived here,
probably due to the meeting of compatible intermediary hosts and
environmental conditions similar to those of the region of its origin
(Novaes et al., 1999). The groups most vulnerable to this infection are
children and pregnant women, due to the forms of contagion and also
because these are risk groups more prone to reinfection (Othman and
Soliman, 2015; Webster et al., 2013).
Schistosomiasis arrived in Brazil in the middle of the 16th century,
L.d.P. Siqueira et al. Acta Tropica 176 (2017) 179–187

Table 1
Epidemiological Picture of schistosomiasis by region in Brazil.
Source: ADTASUS (2016).

Region Population Number of exams Positive Number of people

assessed performed results treated

North 27,332 17779 448 448

Northeast 1,081,458 804,138 43,246 36,438
Southeast 600,757 445,218 16,248 15,348
Southern 155 112 4 4
TOTAL 1,709,702 126,7247 59,946 52,238

PCE Data – Control Program of Schistosomiasis in the last five years (2011–2016).

spreading from the 1920s, with the onset of internal migrations.

Currently, Brazil is considered one of the main areas of distribution of
the disease worldwide, not only due to the vastness of its endemic zone
and the existence of large numbers of patients with severe forms of the
disease, but also because of the spread of this disease to other areas of
the country, until then uninfected. The transmission of schistosomiasis
in Brazil is active in 16 states, reaching mainly the region among
Paraíba, Bahia and Minas Gerais, infesting about 10 million Brazilians,
including endemic regions and isolated foci (Novaes et al., 1999). In
Table 1, according to the DATASUS database, one can observe the
epidemiological picture of schistosomiasis by regions of Brazil.
Contamination occurs through exposure to polluted water in the
endemic region and is acquired when people bathe in fresh water, and,
to a lesser extent, when they are crossing contaminated rivers
(Jauréguiberry et al., 2010; Webster et al., 2013). A brief contact is
sufficient for contamination, only one to five minutes may be sufficient
to allow transcutaneous penetration of the cercariae. Cercarial derma-
titis appears within 24 h after exposure. Itching by itself may be the
only sign. The eruption lasts for a few hours before spontaneously
disappearing (Jauréguiberry et al., 2010).
According to WHO, in tropical and subtropical areas schistosomiasis
is only second to malaria in terms of the number of cases, socio-
economic importance, and public health (Santos, 2011).
The infection is mainly diagnosed by demonstrating evidence of
parasitological infestation through serological testing or molecular
methods using samples such as feces, urine, blood, or other body fluids
and tissue species. However, these test methods have their own lim- Fig. 1. Schistosome lifecycle.
itations in assessing the severity of morbidity. Another method of Source: Olveda et al. (2014).
parasitic diagnosis is by imaging, such as ultrasound, computed tomo-
graphy, and magnetic resonance, which are considered crucial not only the snail is the intermediary host, where the asexual cycle occurs (Sah
to diagnose the disease but also to assess the severity of the disease et al., 2015). Only certain species of snails belonging to the genus
process and its complications in target organs. The clinical and imaging Biomphalaria (S. mansoni), Bulinus (S. haematobium), or Oncomelania
characteristics of the disease may mimic other infectious diseases as (S. japonicum) can transmit the species Schistosoma.
well as non-infectious diseases (Sah et al., 2015). The positive ser- The pathogenesis of human schistosomiasis (Fig. 1) begins when
ological diagnosis for schistosomiasis is associated with hyper- eggs intended to exit the body through feces or urine, become in-
eosinophilia, approximately three weeks after the beginning of the corporated into the tissues of the intestine or human bladder (Merrifield
symptomatology (Jauréguiberry et al., 2010; Sah et al., 2015). The et al., 2016).
eosinophil count is usually above normal limits during infection; Initially, the disease is asymptomatic and can progress to extremely
however, the onset of eosinophilia is delayed compared to the ap- severe clinical forms and lead to death (Santos, 2011; Santos et al.,
pearance of symptoms (Jauréguiberry et al., 2010). 2012). Part of the eggs eliminated by the parasite leave the body
Schistosomiasis also causes a negative impact on health, as a con- through the feces and the other part is retained in the organs (Sah et al.,
sequence of non-specific manifestations such as anemia, exercise in- 2015; Santos, 2011). These trapped eggs subsequently induce in-
tolerance, malnutrition, and learning difficulties (Gazzinelli et al., flammation, granulomas, and fibrosis leading to a number of clinical
2015). sequelae including hepatic fibrosis and hepatosplenomegaly, hema-
turia, bladder fibrosis, and obstruction, hydronephrosis, and chronic
2.1.1. Parasite lifecycle and physiopathology renal disease (Merrifield et al., 2016).
The worms that cause schistosomiasis belong to two phyla: Acute schistosomiasis is characterized by an allergic reaction to the
Nematoda (nematodes or roundworms) and Platyhelminthes (flat- migration and maturation of Schistosoma larvae. The severity of the
worms) (Lee et al., 2014). Shistosomes are dioecious, that is, they have clinical condition is proportional to the parasite load and the immune
male and female worms. Flatworms have complex life cycles and cause response to the parasite antigens (Jauréguiberry et al., 2010).
disease in approximately 200 million people, with 300,000 deaths per The adult forms inhabit the mesenteric vessels of the host and the
year, mainly in sub-Saharan Africa (Lee et al., 2014; Sah et al., 2015). intermediary forms develop in aquatic gastropod snails of the genus
The primary host, where the sexual cycle occurs, is the man, where, Biomphalaria (Malhado et al., 2016). Adult worms dwell in pairs in

181
L.d.P. Siqueira et al. Acta Tropica 176 (2017) 179–187

terminal mesenteric plexus venules that drain blood into the intestinal reactions such as liver and kidney damage, convulsions, psychoses,
wall, especially the sigmoid colon and other portions of the human visual and auditory hallucinations, confusional states, and other un-
large intestine (Lee et al., 2014; Santos, 2011). Each day, about 300 desirable effects on the central nervous system (Novaes et al., 1999).
eggs are eliminated by the female inside the venules; the presence of a
lateral spine is the most prominent feature of these eggs (Santos, 2011).
3.1. Praziquantel
Inflammation, caused by the presence of the eggs in the host, can result
in rupture of the venule wall, releasing the eggs into the perivascular
Praziquantel (PZQ), discovered in 1972, was first developed for
tissues and finally into the intestinal lumen (Lee et al., 2014; Santos,
veterinary use against cestode. It was later used for treatment of human
2011).
schistosomiasis, the first anthelmintic to meet WHO requirements
After passing through the intestinal mucosa, the eggs are eliminated
(Fallon et al., 1996; Kumar and Gryseels, 1994; Malhado et al., 2016;
with the feces and, when they are dragged into the surface waters, they
Meister et al., 2016; Olveda et al., 2016; Santos, 2011).
release their miracidia, which swim for a few hours until they find the
In the years following its first synthesis in the mid-1970s, the effi-
aquatic mollusks of the genus Biomphalaria (Santos, 2011). In addition,
cacy and spectrum of PZQ action against various trematode and cestode
the larvae are transformed into primary sporocytes, which, by multi-
infections were evaluated in order to obtain the effective dose for
plying their germ cells, produce secondary sporocytes. Each secondary
treatment, 40 mg/kg (Jauréguiberry et al., 2010; Kumar and Gryseels,
sporocyte will produce a large number of cercariae, which are released
1994; Olds, 2003; Othman and Soliman, 2015). The PZQ is a pyrazine-
into the water and can survive up to two days, being the infecting form
isoquinoline derivative, a chiral compound with a chiral carbon center
for humans (Sah et al., 2015; Santos, 2011).
(Fig. 1), practically insoluble in water, moderately soluble in ethanol,
After penetration into human skin, cercariae become schistoso-
but very soluble in chloroform and dimethylsulfoxide (Malhado et al.,
mules, which are susceptible to the attack of the cellular effector re-
2016; Othman and Soliman, 2015; Ridi and Tallima, 2013). It is a high-
sponse mediated by antibodies that recognize antigens expressed on
spectrum anthelmintic used in the treatment of all known species of
their surface, as they alter their biochemistry allowing them to escape
schistosomiasis and some species of cestodes and trematodes (Cheng
from the immune system of the host (Santos, 2011).
et al., 2009; Dayan, 2003; Dinora et al., 2005; Farias, 2013; Kumar and
The larvae that are not destroyed can enter the vessel and are taken
Gryseels, 1994; Malhado et al., 2016; Olds, 2003).
to the heart and lungs. In nine days they migrate to the liver, where
At the time of its introduction as an alternative to drug therapy, the
they feed and develop, reach adulthood, and finally reach the mesen-
cost of PZQ was a major obstacle to its mass distribution, but in 1983
teric veins, where they copulate and begin the production of eggs.
the Korean company Shin Poong entered the market with a new process
These can be retained in the organs or can be eliminated by the feces,
and caused a considerable price reduction (Cioli et al., 2014; Olds,
being the eggs of S. haemotobium eliminated by the urine. Adult worms
2003; Othman and Soliman, 2015). Currently, the average cost of PZQ
can render their integument resistant to immunoregulatory effector
is about $0.20 per treatment, while approximately the same amount is
mechanisms that cleave immunoglobulins and inhibit the action of
spent for the distribution of drugs (Cioli et al., 2014).
lymphocytes and mast cells (Lee et al., 2014; Santos, 2011).
Nowadays, PQZ is commercially available in its racemic form, i.e.,
The acute phase is usually asymptomatic, and in the chronic phase
equal mixtures of two enantiomers of a chiral molecule (Cioli et al.,
the most common manifestations of this disease are fever, chills,
2014; Farias, 2013; Meister et al., 2016). The (R)-Praziquantel con-
weakness, weight loss, headaches, nausea, vomiting, diarrhea, hepato-
formation is what has antihelmintic activity, whereas the (S)-Prazi-
megaly, splenomegaly, and eosinophilia. Intestinal neoplasia and
quantel enantiomer is ineffective (Campos, 2009; Farias, 2013). Com-
granulomatous diseases of the intestine are considered to be ulcerative
mercially available proprietary medicinal products are Cestox® and
colitis (Santos, 2011).
Cisticid® (Santos, 2011) (Fig. 2).
Children are a high-risk group in schistosomiasis, since they are
Over the past 20 years, praziquantel (PZQ) and albendazole (ABZ)
generally subjected to more rapid and intense reinfection, as well as
have also been used in the treatment of common helminth diseases of
being more sensitive to praziquantel therapy, preventing or reversing
the nervous system, neurocysticercosis, in developing countries of Latin
the effects of the disease (Kumar and Gryseels, 1994).
America, Asia, and Africa (Dolar et al., 2012). The antihelminthic drugs
have high efficacy, good safety margins and administration versatility
3. Main forms of treatment
(Cioli et al., 2014; Dolar et al., 2012; Othman and Soliman, 2015;
Redman et al., 1996). A disadvantage of this drug is due to the lack of
The first treatments for schistosomiasis were performed with po-
efficacy against the immature forms of the parasite and reports of re-
tassium and antimony tartrate, emetic tartar, introduced in 1918, fol-
sistance to the drug, its greatest use is among affected individuals and
lowed by sodium and antimony dimercaptosuccinate and sodium and
not to prevent reinfection (Cioli et al., 2014; Othman and Soliman,
antimony di-(pirocatechol-2,4-disulphonate), known as stibophen (Katz
2015).
and Coelho, 2008; Novaes et al., 1999). In the following years, other
After oral administration, PZQ undergoes a large first pass meta-
antimony salts were introduced into medical clinics, such as sodium
bolism in the liver, approximately 15 min after oral administration,
antimonylgluconate (Triostib®), antimony-bis-pyrocatechn sodium dis-
ulfonate (Stibofen®), thiomelate sodium antimony (Anthiomaline®), and
antimony gluconate (Triostan®), always parenterally administered (Katz
and Coelho, 2008). The antimony salts, although acting effectively
against the three main species of the genus Shistosoma, S. mansoni, S.
haematobium and S. japonicum, are no longer used in the treatment of
this helminth because they cause numerous side effects, such as
thrombocytopenia and other blood dysplasias (Novaes et al., 1999).
1-N-diethylamino-ethyl-amino-4-methyl-9-thioxanthone hydro-
chloride, the lucantone, and its main metabolite, 1-Nb-diethylami-
noethylamino-(Hydroxymethyl)-9-thioxanthone, the hicantone, are ef-
fective, specifically against S. mansoni and S. haematobium, and also the
drug 1-(5-nitro-2-thiazolyl) imidazolidine-2-one, oniridazole, is effec-
tive against S. haematobium and S. japonicum. These drugs are no longer
Fig. 2. Chemical structure of praziquantel.
used in schistosomiasis drug therapy because they present adverse

182
L.d.P. Siqueira et al.
mainly through CYP450 3A4 (Dayan, 2003; Dinora et al., 2005; Meister
et al., 2016).
Another characteristic of this drug is the high efficacy of the treat-
ment in the initial period of infection, since the parasite is more sus-
ceptible during the first days, and later this susceptibility decreases
until the 28th day, increasing in the 6–7 week of infection. Thus, a low
activity against the treatment of individuals with the presence of the
immature parasite is justified (Cioli et al., 2014; Jauréguiberry et al.,
2010).
The anti-helminth action of PZQ has not been fully understood yet;
however, studies presume that its activity is due to the action on the
tegumentary and muscular tissue, causing contractions in the parasite
that are followed by its death (Cioli et al., 2014; Dayan, 2003; Ridi and
Tallima, 2013). Some authors refer to the action of PZQ on inhibition of
the Na+/K+ pump of the schistosomes, involving mainly Ca2+ (Novaes
et al., 1999; Ridi and Tallima, 2013; Santos, 2011). As a result, it in-
creases the permeability of the helminth membrane to monovalent and
bivalent cations, mainly calcium (calcium influx in all parasites), which
leads to the intensification of muscular activity, followed by contraction
and spastic paralysis.
As a consequence, helminths detach from host tissues (Cioli et al.,
2014; Novaes et al., 1999; Santos, 2011). The structural changes of the
PZQ-induced integuments occur in the following sequence: depolar-
ization of the microtrabecular network, followed by vacuolization and
then surface erosion (Redman et al., 1996; Santos, 2011). These effects
damage muscle function and integument structure resulting in death of
the parasite. PZQ also inhibits, at low concentrations, egg production by
female parasites (Santos, 2011).
After approximately four weeks of treatment (40 mg/kg) the effects
of PQZ can be observed by the excretion of eggs from the parasite (Cioli
et al., 2014). The cure rate can be between 60 and 90%. The other cases
are of mild intensity and cannot be detected by the common para-
sitological methods (Cioli et al., 2014; Kumar and Gryseels, 1994). In
the latter case, the persistence of antibodies, such as IgM, after treat-
ment is a common observation. To ensure a complete cure for this
condition, in cases in which the individual is not exposed to continuous
transmission, dosage increases and changes thereof are necessary, e.g.
30 mg/kg twice daily, for 2–3 consecutive days (Kumar and Gryseels,
1994).
The standard treatment of schistosomiasis is done with a single oral
dose of 40 mg/kg body weight that is effective against S. haematobium,
S. mansoni, and S. Intercalatum (Campos, 2009; Cioli et al., 2014).
However, in the treatment of severe infections, the dosage increases,
with two doses of 25 or 30 mg/kg given at intervals of 4 h, i.e., the total
dose is 50 or 60 mg/kg. The side effects are of low intensity and tem-
porary, such as abdominal pain, headache and drowsiness (Campos,
2009).
For the treatment of schistosomiasis in children, the usual dose is
also 40 mg/kg; however due to the difference in weight (child/adult),
the correct dosage is most often not met, since there are few dosage
variations in the market. Another negative point of the tablet dosage
form for administration to children, in addition to dosage adaptation is
the bitter taste of the drug. However, the development of pharmaceu-
tical forms containing the PZQ as the active principle becomes chal-
lenging due to the hydrophobicity of the drug (Malhado et al., 2016).
When the central nervous system (CNS) is attacked, some experts
recommend Praziquantel with corticosteroids simultaneously for the
treatment of neuroinflammatory sequelae caused by schistosomiasis. It
is also recommended when the antiparasitic treatment induces some
hypersensitivity reaction, presenting characteristics that include head-
ache, hemiparesis, encephalopathy, convulsions, and cerebellar signs
(Berkowitz et al., 2015; Jauréguiberry et al., 2010).
3.2. Oxamniquine
Richards and Foster (1969) and Baxter and Richards (1971),
183
Acta Tropica 176 (2017) 179–187
working at Pfizer Laboratories (Sandwich, England), described a novel
series of 2-amino-methyl-tetrahydroquinoline derivatives, which
showed marked schistosomicidal activity, (Katz and Coelho, 2008), and
the use of oxamniquine (OXA), oxamniquine-1,2,3,4-tetrahydro-2-
(isopropylamino) methyl (−) methanol 7-nitro-6-nitro-quinoline. Ox-
amniquine is activated in Schistosoma via the sulfotransferase me-
chanism, after which oxamniquine binds to the DNA (Albonico et al.,
2015). This drug has been commercially referred to as Mansil®, which is
a combination of the words “mansoni” and “Brazil”, where the first
clinical trials with this drug were performed (Katz and Coelho, 2008).
The main limitation of OXA is that it is not active against S. hae-
matobium or S. japonicum, a fact that discouraged its use outside South
America, the only place where S. mansoni is prevalent. This drug
proved to be at least as good as PZQ, sharing its advantages from a
single oral administration and mild side effects (Cioli et al., 2014).
Some cases of resistance to OXA have been reported, leading to
studies about its cause, by isolating strains of S. mansoni, which were
highly refractory to the drug. Genetic crosses between sensitive and
resistant schistosomes led to the conclusion that resistance to OXA oc-
curs through recessive traits controlled by a simple autosomal gene.
Thus, it suggests the existence of a schistosomical factor essential for
converting the prodrug OXA into the active compound. A number of
other biochemical data confirms this hypothesis and predict that a
parasitic sulfotransferase is the enzyme activator and that the loss of its
function is the cause of resistance to OXA (Cioli et al., 2014; Ridi and
Tallima, 2013).
This hypothesis was recently confirmed through a linking mapping
that identified the S. mansoni sulfotransferase gene and allowed crys-
tallography, enzyme analysis, and the analysis of its interaction with
the drug, representing an elucidation of its mechanism of action (Cioli
et al., 2014; Ridi and Tallima, 2013). According to Katz and Coelho
(2008), oxamniquine showed a mechanism of action related to the
anticholinergic effect, which increases parasite motility as well as in-
hibition of nucleic acid synthesis.
When administered orally, it is more effective against males than
females. The dose of oxamniquine is 50 mg/kg once daily, or two to
three doses of 20 mg/kg to obtain a cure range of 80–90% (Ridi and
Tallima, 2013). However, it is only effective in the case of S. mansoni
infection, which prevents the occurrence of chronic S. mansoni infec-
tion and posture (Jauréguiberry et al., 2010).
Oxamniquine is used in large scale only in Brazil. For the rest of the
world, a single drug is in use for the treatment of schistosomiasis:
praziquantel (Ridi and Tallima, 2013).
3.3. Antimalarics with action on schistosoma
Artemisinin derivatives are known for their antimalarial activity,
but have also been reported for presenting antischistosomal activity. In
general, these types of compounds are more active against the im-
mature form of the Schistosome than against adults – the opposite of the
PZQ – a feature that indicates combined treatments as their optimal use.
Results of clinical trials show that artesunate alone presents lower cure
rates when compared to PZQ, whereas the combination of a prazi-
quantel-artemisinin derivative is more effective than PZQ itself (Cioli
et al., 2014; Jauréguiberry et al., 2010; Ridi and Tallima, 2013).
A limitation for the use of artemisinin against schistosomiasis is the
risk that it may favor the development of drug-resistant plasmodia in
co-endemic areas (Cioli et al., 2014).
Another antimalarial drug that has been reported for presenting
antischistosomal activity is mefloquine (Cioli et al., 2014; Ridi and
Tallima, 2013). As with artemisinin derivatives, the activity against
immature Schistosoma is higher than against adults (Cioli et al., 2014).
Its dosage ranges from 200 to 400 mg/kg, administered orally. Studies
have shown a 70–100% reduction in parasite load (Ridi and Tallima,
2013).
The antimalarial drug artemether, a methoxy derivative of
L.d.P. Siqueira et al.
artemisinin, is administered orally in a single dose of 400 mg/kg. Tests
on mice showed a reduction of 70–80% in the total parasitic load (Ridi
and Tallima, 2013).
Trioxamines, a molecule containing 1,2,4-trioxane and a 4-amino-
quinoline, were initially developed for the treatment of malaria, but
due to their double mechanism of action, such as alkylation of the heme
group and inhibition of hemoglobin formation, they act against
Schistosoma mansoni (Ridi and Tallima, 2013).
3.3.1. Furoxan
The antioxidant defenses of vertebrates are dependent on two en-
zymes: glutathione reductase and thioredoxinareductase. The schisto-
somes only contain a single enzyme, multifunctional aselenocysteine,
thioredoxin glutathione reductase (TGR) (Cioli et al., 2014; Rai et al.,
2009).
This enzyme is essential for the survival of the parasite and has been
the subject of intense studies to increase the capacity of identification of
oxadiazole-2-oxides as a class of potential schistosomicidal agents (Cioli
et al., 2014; Rai et al., 2009). One of these compounds, furoxan, showed
activity in vitro against young adults and worms in μM concentrations,
and was highly effective in vivo when given once daily for five days
through intraperitoneal injections, having a slightly higher toxicity than
PZQ for Mammalian cells (Cioli et al., 2014).
4. Research of new molecules for treatment of schistosomosis
Despite the fact that praziquantel is used as the treatment of choice
in schistosomiasis, the development of resistance has already been
verified in some strains (sporadic cases), presenting the need to search
for new schistosomicidal agents (Carvalho et al., 2015; Oliveira et al.,
2014; Doenhoff and Pica-Mattoccia, 2006; Penido et al., 2007; Ribeiro-
Dos-Santos et al., 2006). This research is mainly performed by the re-
search of the antiparasitic activity of natural compounds (Moraes,
2012; Oliveira et al., 2014; Carvalho et al., 2015) and by the synthesis
of new series of compounds with anthelmintic activity (Penido et al.,
2007; Moreira et al., 2007; Spivak et al., 2014).
The main target for the development of these agents is the
Schistosoma integument, which plays a crucial role in the survival of
the parasite and is a barrier against the immune system response of the
host (Moraes, 2012; De Moraes et al., 2012). A study reported good
schistosomicidal activity of Glycyrrhiza inflata (Fabaceae) extract, with
action against S. mansoni adult worms, causing damage to the integu-
ment of the worm and inhibiting egg laying (Carvalho et al., 2015).
The development of new drugs is increasingly important in the face
of potential resistance to currently available treatments for schistoso-
miasis, and the absence of an effective vaccine (Lee et al., 2014). The
process of discovery and development of drugs is very complex, being
linked to the scientific and technological roots that the sector provides
(Cioli et al., 2014; Dias et al., 2013). It is important to encourage the
establishment of appropriate mechanisms to intensify investments in
infrastructure and personnel qualifications within a strategic vision that
contemplates continuity (Dias et al., 2013).
Unfortunately, the therapeutic options currently available for the
treatment of helminths are not always effective in all stages of the life
cycle of these parasites (Kyelem et al., 2015). They are limited, in-
sufficient, and present a series of problems, such as low efficacy, high
toxicity, and the emergence of resistant strains (Dias et al., 2013). Some
parasites that infect humans present long life expectancy and high re-
production rate. In other words, control of the proliferation of helminth
that cause NTDs will only be effective if they are maintained in the long
term (Kyelem et al., 2015).
This scenario is further aggravated by the lack of investment and
innovation in drug R & D programs, which reflect the extremely small
number of drugs that have made to the market in recent decades (Cioli
et al., 2014, Dias et al., 2013). Because these diseases affect mainly low-
income people, they do not have high purchasing power, so the
184
Acta Tropica 176 (2017) 179–187
pharmaceutical industry does not invest in this area (Dias et al., 2013).
The synthesis of praziquantel (PZQ) has attracted the attention of
various groups as an efficient product, with reduction of steps and in-
crease of yield, substantially reducing the cost for mass distribution of
the drug. A line of research for new drugs for the treatment of schis-
tosomiasis has been studied through the synthesis of praziquantel
analogues. The synthetic pathway has been designed to provide struc-
turally diverse analogues for a better structure-activity relationship. A
total of nineteen PZQ analogues were discovered/synthesized with
structural variations in amide, piperazine and aromatic parts (Sadhu
et al., 2012).
Among all the new analogues tested for desired activity, one tetra-
dimethoxy analogue and two tetrahydro-b-carboline analogues showed
moderate activity against adult Schistosoma mansoni (Sadhu et al.,
2012). Sadhu et al. (2012) performed the in vitro test of these analogues
in cultures of adult S. mansoni, presenting relevant activities in com-
parison to PZQ.
Another line of research for the treatment of schistosomiasis in-
volves the development of vaccines (Cioli et al., 2014; Othman and
Soliman, 2015). Currently, there are no pre-emptive vaccines licensed
for any human helminth infection (Hortez et al., 2016). However, there
are studies involving vaccine formulations with the purified antigen,
attenuated cercariae and excretory-secretory antigens (Othman and
Soliman, 2015).
The promotional program launched in 1990 by UNICEF/UNDP/
World Bank/WHO for the Tropical Diseases Research and Training re-
sulted in a list of six vaccine candidates for schistosomiasis. Some of
these candidates have produced recombinant antigens, and two have
reached the stage of clinical trials: S. haematobium 28 kDa antigen
glutathione S-transferase (ShGST) and S. mansoni 14 kDa of the fatty
acid binding protein of (Sm14-FABP) (Santini-Oliveira et al., 2016).
The discovery of Sm14 followed by encouraging results from ex-
tensive animal vaccination studies established the validity of Sm14
while stable expression of the recombinant molecule (Sm14r) has made
it a promising candidate to obtain the vaccine. Sm14 is the only vaccine
candidate against schistosomiasis developed in an endemic country
(Brazil) to reach the level of clinical trials. In the clinical trials, no
serious adverse events were observed after three antischistosomiasis
vaccinations of 20 healthy male adults from a non-endemic area with
Sm14 formulated with the adjuvant GLASE, the first synthetic adjuvant
approved for use in human trials. The synthetic was administered at 30-
day intervals (Santini-Oliveira et al., 2016).
5. Pharmaceutical industries X negligenced diseases
The pharmaceutical industry has always kept pace to produce and
market new products. In contrast, the number of drugs used to treat
NTDs is very small, and it is clear that the investment in R & D for such
diseases is inadequate (Santos et al., 2012; Dias and Dessoy, 2009).
In the last decade, pharmaceutical companies, governments, and
world health organizations under the leadership of WHO have com-
mitted to large-scale donations of anti-helminthic drugs, including
ivermectin (IVM), praziquantel (PZQ), albendazole (ALB), and me-
bendazole (MEB). There is also a monitoring system by the pharma-
ceutical industry to detect any changes in the efficacy of the anthel-
mintic drug. In 2013, 718 million people at risk were treated with more
than 1.3 million anti-helminthic tablets (Albonico et al., 2015). In
Table 2, we can verify the main pharmaceutical industries that produce
the most relevant drugs in the treatment of schistosomiasis: prazi-
quantel and oxamniquine.
The resources of the pharmaceutical industry dedicated to this
concept are relatively small and there are good reasons for the industry
to be reluctant to invest in the development of this type of therapy.
Pharmaceutical companies face greater pressure than in the past to
ensure that a new drug design succeeds in clinical practice. The new
drug must be highly effective. It must be clinically more effective than
L.d.P. Siqueira et al.
Table 2
Main laboratories that produce the main anti-schistosomiasis drugs.
Industry Active principle Comercial name Dosage
Merck® Praziquantel Cestox® 150 mg
Cisticid® 600 mg
Farmanguinhos Praziquantel – 600 mg
Pfizer® Oxaminiquine Mansil® 250 mg
the standard already used, protected by patent, and have sufficient fi-
nancial potential to help sustain ongoing research and development.
Some new drugs, however, fail to meet these requirements in order to
obtain financing for their development (Tilp et al., 2013).
Studies by the Drugs for Neglected Diseases initiative (DNDi) and
the organization Doctors Without Borders, on the evolution of research
and development in the area of neglected diseases found out that
among 756 new drugs approved from 2000 to 2011, only 3.8% were for
neglected diseases. Of these, only four were new chemical entities, and
three of these were indicated for malaria treatment and none for tu-
berculosis or other neglected diseases (Dias et al., 2013).
Currently, some pharmaceutical companies have research and de-
velopment units and/or partnerships with major university centers fo-
cusing on the promotion of neglected diseases (Cohen et al., 2014).
Examples of actions taken to mitigate the impact of NTDs are the alli-
ance between WHO and GlaxoSmithKline (GKS) with the donation of
400 million tablets per year of albendazole for the treatment of children
with intestinal worms. Another partnership is with Sanofi, which gives
donations of unlimited amounts of eflornithine, melarsoprol, and pen-
tamidine for the treatment of African trypanosomiasis. Bayer, through
2017, increased its donation to five million tablets for the treatment of
American and African trypanosomiasis, while Johnson & Johnson is
expanding its donation of 50 million mebendazole tablets to 200 mil-
lion per year. Novartis collaborates through donations of rifampicin,
dapsone, and clofazimine for the treatment of leprosy. Pfizer donates
azithromycin for the treatment of trachoma and Merck KGaA con-
tributes to the control of schistosomiasis with a donation of 200 million
praziquantel tablets (Dias et al., 2013).
6. Control policies for neglected diseases
Since the late 1990s, there has been an increase in funding for de-
velopment of drugs for neglected diseases. In the period from 2009 to
2013 new approvals for drug development were registered, including
new chemical entities, fixed-dose combination, vaccines, and formula-
tions. Malnutrition and HIV, both for pediatric are among the most
neglected diseases with greater financial support and products in test
phase III. Funding for the development of new drugs for the treatment
of neglected diseases is supported mainly by philanthropic organiza-
tions and the public sector, where the developed drug must be made
available to the population in the appropriate dosage and pharmaceu-
tical form, in addition to an affordable value for the population, when it
is not possible to deliver the medicines free of charge (Cohen et al.,
2014).
DNDi researches and develops new treatments and has as its
founding partners the Pasteur Institute in France, the Oswaldo Cruz
Foundation (FIOCRUZ) in Brazil, the Ministry of Health of Malaysia,
and the clinical research institutes in India and Kenya. In 2003, the first
National Conference on Medicines and Pharmaceutical Assistance was
organized in Brazil. Propositions were adopted that aimed to create a
specific public policy for R & D of drugs and medicines according to
health needs following epidemiological and social criteria (Santos et al.,
2012).
Currently, over three million dollars are spent on neglected diseases;
however, this is a relatively small amount when compared to research
and development on non-neglected diseases. Between 2000 and 2013,
185
Acta Tropica 176 (2017) 179–187
43 new product approvals for neglected diseases were identified.
Among them, three were new molecular entities, seven new formula-
tions, seven vaccines, seventeen fixed-dose combination products, and
nine new indications for existing drugs (Cohen et al., 2016).
The area of neglected diseases has been a priority of the Brazilian
government, which instituted the Research and Development Program
on Neglected Diseases, focusing on seven diseases: dengue, Chagas
diseases, leishmaniosis, leprosy, malaria, schistosomiasis, and tu-
berculosis (OMS, 2010). Government incentives for R & D in this area
are increasing and are around R$ 75 million per year. A good part
comes from the Ministry of Science and Technology through its two
main funding agencies: the National Council for Scientific and Tech-
nological Development (CNPq) and the Financier of Studies and Pro-
jects (FINEP), which in 2008 invested More than R$ 25 million in R & D
projects for neglected diseases. This places Brazil in a prominent posi-
tion, occupying sixth place in the ranking of the countries that invest
the most in this segment (Santos et al., 2012).
In 1986, WHO announced that FIOCRUZ as a collaborating center
for basic and applied research in schistosomiasis, including financial
support for some activities. This nomination encouraged the
“Integrated Schistosomiasis Program of the Oswaldo Cruz Foundation”
(PIDE/FIOCRUZ) to be officially signed in 2007. For 21 years, the re-
searchers of the project published 910 scientific articles and 16 book
chapters, as well as the training of human resources with 64 disserta-
tions and 42 theses completed. Currently, seven researchers who are
members of PIDE are members of the Technical Advisory Committee of
the Schistosomiasis Program of the Secretariat of Health Surveillance
(Brasil, 2010).
7. Conclusion
Schistosomiasis, because it affects mainly the poorest segment of the
population, has a lack of interest from the pharmaceutical industry due
to the low financial return. Thus, the advancement of therapies for this
disease is reduced. However, there is a growing incentive in this area
for the governments of regions and countries with high incidences of
the disease aimed at changing the parasitological situation of society
and, consequently, reducing morbidity expenditures.
Despite efforts by WHO and other agencies for large-scale treatment
with PZQ in the affected areas, it must be ensured that everyone re-
ceives appropriate treatment, avoiding increased resistance to the drug.
Thus, public policies must be more effective, drawing attention to this
problem, and improving the control and endemic character of the dis-
ease.
References
Albonico, M., Levecke, B., Loverde, P.T., Montresor, A., Prichard, R., Vercruysse, J.,
Webster, J.P., 2015. Monitoring the efficacy of drugs for neglected tropical diseases
controlled by preventive chemotherapy. J. Glob. Antimicrob. Resist. 3 (1), 229–236.
Arruá, E.C., Ferreira, M.J.G., Salomon, C.J., Nunes, T.G., 2015. Elucidating the guest-host
interactions and complex formation of praziquantel and cyclodextrin derivatives by
13C and 15N solid-state NMR spectroscopy. Int. J. Pharm. 496, 812–821.
Baxter, C.A.R., Richards, H.C., 1971. Schistosomicides 1 derivatives of 2-aminomethyl-1,
2, 3, 4- tetrahydroquinoline. J. Med. Chem. 14 (1), 1033–1042.
Bergquist, R., Yang, G.-J., Knopp, S., Utzinger, J., Tanner, M., 2015. Surveillance and
response: tools and approaches for the elimination stage of neglected tropical dis-
eases. Acta Trop. 141, 229–234.
Berkowitz, A.L., Raibagkar, P., Pritt, B.S., Mateen, F.J., 2015. Neurologic manifestations
of the neglected tropical diseases. J. Neurol. Sci. 349, 20–32.
Brasil Ministério Da Saúde, 2010. Departamento de Ciéncia e Tecnologia, Secretaria de
Ciéncia, Tecnologia e Insumos Estratúgicos. Doenêas negligenciadas: estratúgias do
Ministúrio da Saçde. Revista de Saçde Pçblica 44 (1), 200–202 ISSN 0034-8910.
Campos, F.S., 2009. Desenvolvimento de Hidrogéis de Dextrano contendo Praziquantel.
72f. Dissertação. Universidade Estadual Paulista, Araraquara.
Caplan, A., Zink, A., 2014. Adverse event management in mass drug administration for
neglected tropical diseases. Clin. Ther. 36 (3), 421–424.
Cardoso, D.N., Santos, M.J.G., Soares, A.M.V.M., Loureiro, S., 2015. Molluscicide baits
impair the life traits of Folsomiacândida (Collembola): possible hazard to the popu-
lation level and soil function. Chemosphere 132 (1), 1–7.
Carvalho, L.S.A., Geraldo, R.B., De Moraes, J., Silva Pinto, P.L., De Faria Pinto, P., Pereira,
L.d.P. Siqueira et al.
O.S., Da Silva Filho, A.A., 2015. Schistosomicidal activity and docking of Schistosoma
mansoni ATPDase 1 with licoflavone B isolated from Glycyrrhiza inflata (Fabaceae).
Exp. Parasitol. 159, 207–214.
Cavalcanti, M.G., Silva, L.F., Peralta, R.H.S., Barreto, G.M., Peralta, J.M., 2013.
Schistosomiasis in areas of low endemicity: a new era in diagnosis. Trends Parasitol.
29 (2), 75–82.
Cheng, L., Guo, S., Wu, W., 2009. Characterization andin vitrorelease of praziquantel
from poly (ε-caprolactone) implants. Int. J. Pharm. 377 (1), 112–119.
Cioli, D., Pica-Mattoccia, L., Basso, A., Guidi, A., 2014. Schistosomiasiscontrol: prazi-
quantel forever? Mol. Biochem. Parasitol. 195 (1), 23–29.
Cohen, J.P., Sturgeon, G., Cohen, A., 2014. Measuring progress in neglected disease drug
development. Clin. Ther. 36 (7), 1037–1042.
Cohen, J.P., Silva, L., Cohen, A., Awatin, J., Sturgeon, R., 2016. Progress report on ne-
glected tropical disease drug donation programs. Clin. Ther. 38 (5), 1193–1204.
Dayan, A.D., 2003. Albendazole, mebendazole and praziquantel. Review of non-clinical
toxicity and pharmacokinetics. Acta Trop. 86 (1), 141–159.
De Moraes, J., Nacimento, C., Yamagushi, L.F., Kato, M.J., Nakano, E., 2012. Schistosoma
mansoni: in vitro schistosomicidal activity schistosomicidal activity and tegumental
alterations induced by piplartine on schistosomula. Exp. Parasitol. 132, 222–227.
Dias, L.C., Dessoy, M.A., 2009. Quimioterapia da doença de Chagas: estado da arte e
perspectivas no desenvolvimento de novos fármacos. Quím. Nova 32, 2444–2457.
Dias, L.C., Dessoy, M.A., Guido, R.V.C., Oliva, G., Andricopulo, A.D., 2013. Doenças
Tropicais Negligenciadas: Uma Nova Era de Desafios e Oportunidades. Quím. Nova
36 (10), 1552–1556.
Dinora, G., Julio, R., Nelly, C., Lilian, Y., Cook, H.J., 2005. In vitro characterization of
some biopharmaceutical properties of praziquantel. Int. J. Pharm. 295 (1), 93–99.
Doenhoff, M.J., Pica-Mattoccia, L., 2006. Praziquantel for the treatment of schistoso-
miasis: its use for control in areas with endemic disease and prospects for drug re-
sistance. Expert Rev. Anti Infect. Ther. 4, 199–210.
Dolar, D., Pelko, S., Košutić, K., Horvat, A.J.M., 2012. Removal of anthelmintic drugs and
their photodegradation products from water with RO/NF membranes. Proc. Saf.
Environ. Prot. 90 (1), 147–152.
Fallon, P.G., Tao, L.-F., Ismail, M.M., Bennet, J.L., 1996. Schistosome resistance to pra-
ziquantel: fact or ArtifactZ? Parasitology Today 12 (8), 316–320.
Farias, B.V., 2013. Avaliação Do Equilíbrio de Adsorção e Projeto de Condições de
Separação de Praziquantel por Cromatografia Líquida de Alta Eficiência (CLAE). 91 f.
Dissertação. Departamento de Engenharia Química, Universidade Federal do Ceará,
Fortaleza.
Fenwick, A., 2012. The global burden of neglected tropical diseases. Public Health 126
(1), 233–236.
Frezza, T.F., Gremião, M.P.D., Zanotti-Magalhães, E.M., Magalhães, L.A., Souza, A.L.R.,
Allegretti, S.M., 2013. Liposomal-praziquantel: efficacy against Schistosoma mansoni
in a preclinical assay. Acta Trop. 128 (70), 75.
Frezza, T.F., Souza, A.L.R., Prado, C.C.R., Oliveira, C.N.F., Gremião, M.P.D., Giorgio, S.,
Dolder, M.A.H., Joazeiro, P.P., Allegretti, S.M., 2015. Effectiveness of hyperbaric
oxygen for experimental treatment ofschistosomiasis mansoni using praziquantel-free
and encapsulatedinto liposomes: assay in adult worms and oviposition. Acta Trop.
150, 182–189.
Gabrielli, A.F., Montresor, A., Nicholls, R.S., Ault, S.K., 2013. Progress towards the con-
trol and elimination of neglected tropical diseases in Brazil. J. Pediatr. (Rio. J) 89 (3),
215–6216.
Gazzinelli, M.F., Lobato, L., Andrade, G., Matoso, L.F., Diemert, D.J., Gazzinelli, A., 2015.
Improving the understanding of schistosomiasis among adolescents in endemic areas
in Brazil: a comparison of educational methods. Patient Educ. Couns. 99 (10),
1657–1662.
Gonnert, R., Andrews, P., 1977. Praziquantel: a new broad-spectrum antischistosomal
agent. Z. Parasitenk 52, 129–150.
Hortez, P.J., Brown, A.S., 2009. Neglected tropical disease vaccines. Biologicals 37 (1),
160–164.
Hotez, P.J., Fujiwara, R.T., 2014. Brazil’s neglected tropical diseases: an overview and a
report card. Microbes Infect. 16, 601–606.
Hortez, P.J., Woc-Colburn, L., Bottazzi, M.E., 2014. Neglected tropical diseases in Central
America and Panama: review of their prevalence, populations at risk and impact on
regional development. Int. J. Parasitol. 44 (1), 597–603.
Hotez, P.J., Strych, U., Lustigman, S., Bottazzi, M.E., 2016. Human anthelminthic vac-
cines: rationale and challenges. Vaccine 34 (1), 3549–3555.
Jauréguiberry, S., Paris, L., Caumes, E., 2010. Acute schistosomiasis, a diagnostic and
therapeutic challenge. Clin. Microbiol. Infect. 16 (3), 225–231.
Katz, N., Coelho, P.M.Z., 2008. Clinical therapy of schistosomiasis mansoni: The Brazilian
contribution. Acta Tropica 108, 72–78.
Kumar, V., Gryseels, B., 1994. Use of praziquantel against schistosomiasis: a review of
current status. Int. J. Antimicrob. Agents 4 (1), 313–320.
Kyelem, D., Fischer, P.U., Bratting, N.W., 2015. The diagnostics and control of neglected
tropical helminth diseases. Acta Trop. 120 (1), S1–S3.
Lee, E.F., Young, N.D., Lim, N.T.Y., Gasser, R.B., Fairlie, W.D., 2014. Apoptosis in
schistosomes: toward novel targets for the treatment of schistosomiasis. Trends
Parasitol. 30 (2), 75–84.
Malhado, M., Pinto, D.P., Silva, A.C.A., Silveira, G.P.E., Pereira, H.M., Santos, J.G.F.,
Guilarducci-Ferraz, C.V.V., ViçosA, A.L., Nele, M., Foncesa, L.B., Pinto, J.C.C.S., Calil-
Elias, S., 2016. Preclinical pharmacokinetic evaluation of praziquantel loaded in poly
(methylmethacrylate) nanoparticleusing a HPLC–MS/MS. J. Pharm. Biomed. Anal. 1
(117), 405–412.
Meister, I., Leonidova, A., Kovac, J., Duthaler, U., Keiser, J., Huwyler, J., 2016.
Development and validation of an enantioselective LC-MS/MS method for the ana-
lysis of the anthelmintic drug praziquantel and its main metabolite in human plasma,
blood and dried blood spots. J. Pharm. Biomed. Anal. 1 (118), 81–88.
186
Acta Tropica 176 (2017) 179–187
Merrifield, M., Hotez, P.J., Beaumier, C.M., Gillespiea, P., Strych, U., Hayward, T.,
Bottazzi, M.E., 2016. Advancing a vaccine to prevent human schistosomiasis.
Vaccine. 34, 2988–2991.
Moraes, J., 2012. Antischistosomal natural compounds: present challenges for new drug
screens. Curr. Topics Trop. Med. InTech, Rijeka 333–358.
Moreira, L.S., Pilo-Veloso, D., De Mello, R.T., Coelho, P.M., Nelson, D.L., 2007. A study of
the activity of 2-(alkylamino)-1-phenyl-1-ethanethiosulfuric acids against infection
by Schistosoma mansoni in a murine model. Trans. R. Soc. Trop. Med. Hyg. 101,
385–390.
Noden, B.H., Colf, B.E.V., 2013. Neglected tropical diseases of Namibia: unsolved mys-
teries. Acta Trop. 125 (1), 1–17.
Novaes, M.R.C.G., Souza, J.P., Araújo, H.C., 1999. Síntese do Anti-helmíntico
Praziquantel, a partir da Glicina. Quím. Nova 22 (1), 5–10.
Olds, G.R., 2003. Administration of Praziquantel to pregnant and lactatingwomen. Acta
Trop. 86 (1), 185–195.
Oliveira, R.S., Rehder, V.L.G., Oliveira, A.S.S., Jeraldo, V.L.S., Linhares, A.X., Allegretti,
S.M., 2014. Atividade anti-helmíntico in vitro e in vivo de Baccharis trimera (Less)
DC contra vermes imaturos e Adultos de Schistosoma mansoni. Exp. Parasitol. 139,
63–72.
Oliveira, C.X., Ferreira, N.S., Mota, G.V.S., 2016. A DFT study of infrared spectra and
Monte Carlo predictions of the salvation shell of Praziquantel and β-cyclodextrin
inclusion complex in liquid water. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.
153, 102–107.
Olveda, D.U., Olveda, R.M., McManus, D.P., Cai, P., Chau, T.N.P., Lam, A.K., Li, Y., Ham,
D.A., Vinluan, M.L., Ross, A.G.P., 2014. The chronic enteropathogenic disease
schistosomiasis. Int. J. Infect. Dis. 28, 193–203.
Olveda, R.M., Acosta, L.P., Tallo, V., Baltazar, P.I., Lesiguez, J.L., Estanislao, G.G., Ayaso,
E.B., Monterde, D.B.S., Ida, A., Watson, N., Mcdonald, E.A., Wwu, H., Kurtis, J.D.,
Friedman, J.F., 2016. Efficacy and safety of praziquantel for the treatment of human
schistosomiasis during pregnancy: a phase 2, randomised, double-blind, placebo-
controlled trial. Lancet Infects 16 (1), 199–208.
OMS, 2010. Trabalhando para superar o impacto global das doenças tropicais negli-
genciadas: Primeiro Relatório da OMS sobre doenças tropicais negligenciadas.
Organização Mundial da Saúde, Genebra.
OMS, 2012. Accelerating Work to Overcome the Global Impact of Neglected Tropical
Diseases: A Roadmap for Implementation. World Health Organization, Geneva
(WHO/HTM/NTD/2012.1).
OMS, 2010. Trabalhando para superar o impacto global das doenças tropicais negli-
genciadas: Primeiro Relatório da OMS sobre doenças tropicais negligenciadas.
Organização Mundial da Saúde, Genebra.
Othman, A.A., Soliman, R.H., 2015. Schistosomiasis in Egypt: a never-ending story? Acta
Trop. 148 (1), 179–190.
Penido, M.L.O., Resende, D.M., Vianello, M.A., Bordin, F.H.S., Jacinto, A.A., Dias, W.D.,
Montesano, M.A., Nelson, D.L., Coelho, P.M.Z., Vasconcelos, E.G., 2007. A new series
of schistosomicide drugs the alkylaminoalkanethiosulfuric acids, partially inhibit the
activity of Schistosoma mansoni ATP diphosphohydrolase. Eur. J. Pharmacol. 570,
10–17.
Rai, G., Thomas, C.J., Leister, W., Maloney, D.J., 2009. Synthesis of oxadiazole-2-oxide
analogues as potential antischistosomal agents. Tetrahedron Lett. 50 (1), 1710–1713.
Redman, C.A., Robertson, A., Fallon, P.G., Modha, J., Kusel, J.R., Doenhoff, M.J., Martin,
R.J., 1996. Praziquantel: an urgent an exciting challenge. Parasitol. Today 12 (1),
14–20.
Ribeiro-Dos-Santos, G., Verjovski-Almeida, S., Leite, L.C.C., 2006.
Schistosomiasis—acentury searching for chemotherapeutic drugs. Int. J. Parasitol.
Drugs Drug Resist. 99, 505–521.
Richards, H.C., Foster, R., 1969. A new series of 2-aminomethyltetrahydroquinoline de-
rivatives displaying schistosomicidal activity in rodents and primates. Nature 222,
581–582.
Ridi, R.A.F., Tallima, H.A.M., 2013. Novel therapeutic and prevention approaches for
schistosomiasis: review. J. Adv. Res. 4 (1), 467–478.
Rocha, A.J., 2012. O Impacto Social das Doenças Negligenciadas no Brasil e no mundo.
46f. Monografia. Faculdade de Medicina da Bahia, Universidade Federal da Bahia,
Bahia.
Sadhu, P.S., Kumar, S.N., Chandrasekharam, M., Pica-Mattoccia, L., Cioli, D., Rao, V.J.,
2012. Synthesis of new praziquantel analogues: potential candidates for the treat-
ment of schistosomiasis. Bioorg. Med. Chem. Lett. 22 (1), 1103–1106.
Sah, V.K., Wang, L., Min, X., Rizal, R., Feng, Z., Ke, Z., Deng, M., Li, L., Li, H., 2015.
Human schistosomiasis: a diagnostic imaging focused review of a neglected disease.
Radiol. Infect. Dis. 2 (1), 150–157.
Santini-Oliveira, M., Coler, R.N., Parra, J., Veloso, V., Jayashankar, L., Pinto, P.M., Ciol,
M.A., Bergquist, R., Reed, S.G., Tendler, M., 2016. Schistosomiasis vaccine candidate
Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male
adults. Vaccine 34 (1), 586–594.
Santos, F.L.A., Lyra, M.A.M., Alves, L.D.S., Silva, K.E.R., Rolim, L.A., Gomes, T.C.B.L.,
Ferraz, L.R.M., Lima, A.A.N., Soares-Sobrinho, J.L., Rolim-Neto, P.J., 2012. Pesquisa,
desenvolvimento e inovação para o controle das doenças negligenciadas. Revista de
Ciências Farmacêuticas Básica e Aplicada 33 (1), 37–47.
Santos, F.K., 2011. Desenvolvimento e Caracterização de Carreadores Lipídicos
Nanoestruturados contendo Praziquantel. 83 f. Dissertação. Universidade Estadual
Paulista, Araraquara.
Spivak, A.Y., Keiser, J., Vargas, M., Gubaidullin, R.R., Nedopekina, D.A., Shakurova, E.R.,
Khalitova, R.R., Odinokov, V.N., 2014. Synthesis and activity of new triphenylpho-
sphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in
vitro and in vivo. Bioorg. Med. Chem. 22, 6297–6304.
Steinmann, P., Keiser, J., Bos, R., Tanner, M., Utzinger, J., 2006. Schistosomiasis and
water resources development: systematic review meta-analysis, and estimates of
L.d.P. Siqueira et al.
people at risk. Lancet Infect. Dis. 6, 411–425.
Thetiot-Laurent, S.A., Boissier, J., Robert, A., Meunier, B., 2013. Schistosomiasis che-
motherapy. Angew. Chem. Int. Ed. 53, 17936–17956.
Tilp, C., Kapur, V., Loging, W., Erb, K.J., 2013. Prerequisites for the pharmaceutical in-
dustry to develop and commercialise helminths and helminth-derived product
therapy. Int. J. Parasitol. 43 (1), 319–325.
Tlamçami, Z., Er-Rami, E., 2014. Schistosomiasis control: moroccan experience compared
to other endemic countries. Asian Pac. J. Trop. Dis. 4 (4), 329–332.
Webster, B.L., Diaw, O.T., Seye, M.M., Faye, D.S., Stothard, J.R., Sousa-Figueredo, J.C.,
187
Acta Tropica 176 (2017) 179–187
Rollinson, D., 2013. Praziquantel treatment of school children from single and mixed
infection fociofintestinal and urogenital schistosomiasis along the Senegal River
Basin: monitoring treatment success and re-infection patterns. Acta Trop. 128 (1),
292–302.
Weerakoon, K.G., Gobert, G.N., Cai, P., McManus, D.P., 2015. Advances in the diagnosis
of human schistosomiasis. Clin. Microbiol. Rev. 28, 939–967.
Werneck, G.L., Hasselmann, M.A., Gouvea, T.G., 2011. Panorama dos Estudos e Doenças
Negligenciadas no Brasil. Ciência e Saúde Coletiva 16 (1), 39–62.