Menoufia Medical Journal

: 2018  |  Volume : 31  |  Issue : 1  |  Page : 354--364

Assessment of Echinacea purpurea and mefloquine in treatment of Schistosoma mansoni

Wafaa M El-kersh1, Azza H Mohamed2, Amany A Rady1, Ismail M Moharm1, Ahmed S Mahdy1,  
1 Medical Parasitology Department, Faculty of Medicine, Menoufia University, Egypt
2 Zoology Department, Faculty of Science, Menoufia University, Egypt

Correspondence Address:
Ahmed S Mahdy
Medical Parasitology Department, Faculty of Medicine, Menoufia University


Objective To assess the effect of combined Echinacea purpurea (EP) and mefloquine (MQ) in the treatment of experimental Schistosoma mansoni infection. Background Schistosomiasis is a prevalent parasitic disease in tropical and subtropical areas caused by the flatworm S. mansoni. Several medications are used in the treatment of schistosomiasis. Praziquantel (PZQ) is the drug of choice because of its safety and broad-spectrum activity. Materials and methods The current study was carried out on 120 laboratory-bred Swiss albino female mice. They were classified into six groups: group I (control), group II (PZQ treated), group III (MQ treated), group IV (EP treated), group V (PZQ and EP), and group VI (MQ and EP). Evaluation was done parasitologically using the worm count technique, ova count technique in intestine and liver, and oogram pattern and histopathological examination of liver sections for assessment of granuloma size and diameter. Moreover, electron microscopic changes of the adult worms were evaluated. Results The highest worm burden reduction of male (79.41%), female (82.28%), couples (86.6%), and total (92%) worms was obtained in the combined MQ and EP treated group. The highest reduction in the mean number of ova count/g tissue in either the intestine (93%) or the liver (89%) was detected in MQ and EP treated group. In combined treated groups, the highest percentage of reduction in the immature and mature eggs was detected in the group MQ and EP; it was 9.16 ± 4.11 and 5.25 ± 2.56, respectively. Moreover, there was an increase in the percentage of dead eggs (85.58 ± 6.43). The highest reductions in hepatic granuloma diameter and number were seen in the combination of MQ and EP at 67 and 85%, respectively (P < 0.001). The scanning electron microscopy examination revealed that the tegument of male worms recovered from MQ-treated mice showed loss of spines, severe corrugation, and extensive blebbing, whereas the tegument of the adult males recovered from mice treated with EP showed flattening of tubercles, loss of spines, and extensive blebbing with start of sloughing. Conclusion MQ has effective schistosomicidal properties through reduction of worm burden and tissue egg load. Moreover, EP extract showed promising antischistosomal activity on S. mansoni-infected mice. It is recommended to study the exact mechanism of action of EP on S. mansoni and its possible effects on other parasitic infections.

How to cite this article:
El-kersh WM, Mohamed AH, Rady AA, Moharm IM, Mahdy AS. Assessment of Echinacea purpurea and mefloquine in treatment of Schistosoma mansoni.Menoufia Med J 2018;31:354-364

How to cite this URL:
El-kersh WM, Mohamed AH, Rady AA, Moharm IM, Mahdy AS. Assessment of Echinacea purpurea and mefloquine in treatment of Schistosoma mansoni. Menoufia Med J [serial online] 2018 [cited 2020 Mar 30 ];31:354-364
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Schistosomiasis is a prevalent parasitic disease in tropical and subtropical areas, which accounts for the second place in terms of socioeconomic and public health burden [1],[2]. Pathology associated with Schistosoma mansoni results primarily from the accumulation of parasite eggs giving rise to hepatomegaly that may be superseded by extensive liver fibrosis [3]. Each year schistosomiasis afflicts up to 600 million people in 74 tropical and subtropical countries; of whom, more than 30 million experience associated severe morbidity, causing 155 000 deaths annually, predominantly in the developing world [3].

Several medications are used in the treatment of schistosomiasis, including praziquantel (PZQ), oxamniquine, metrifonate, and antimonials. Current treatment relies on PZQ [4]. The PZQ has stage-dependent susceptibility. It targets the adult worm but has only minor activity against the young immature developing stages (schistosomula) [5],[6]. The PZQ was involved in the global control programs as well as morbidity control strategy, which has greatly reduced the prevalence and intensity of infections [7],[8]. It is quite safe and effective with a single oral dose, producing high cure rate ranging between 60 and 90% in addition to drastic reduction in the number of excreted Schistosoma eggs [9]. The widespread use of PZQ has led to a considerable concern over the emergence of strains of S. mansoni resistant to PZQ [4]. So for controlling schistosomiasis, there is an urgent need to develop a new effective drug.

Over the past few years, the antimalarial drug mefloquine (MQ) was investigated for its schistosomicidal effect and evidenced a reduction in egg burden in S. mansoni-infected mice following its administration [8]. It is a methanol-quinoline drug. As a blood schizonticide, it is very effective against P. falciparum and other Plasmodia infections in malarial endemic areas; it is used for treatment as well as prophylaxis against malaria [10]. MQ also showed high activity against S. japonicum [6] and S. haematobium [9], which highlights a promising broad-spectrum antischistosomal effect.

Plants are an important source of biologically active compounds that can provide components for the development of new drugs [11]. Therefore, examples such as Zingiber officinale [12], Piper cubeta [13], Curcuma longa [14], and Solanum lycocarpum [15] have been studied as natural products with schistosomicidal activity.

Echinacea purpurea (EP) is a perennial medicinal herb with important immunostimulatory and anti-inflammatory properties, especially for the alleviation of cold symptoms. Other biological activities of the plant, such as antioxidant, antibacterial, antiviral, and larvicidal activities, have been reported in previous experimental studies. Different classes of secondary metabolites of the plant, such as alkamides, caffeic acid derivatives, polysaccharides, and glycoprotein, are believed to be biologically and pharmacologically active [16].

There are numerous in-vivo studies on the immunomodulatory and anti-inflammatory effects of EP, which suggest that innate immunity is enhanced by administration of the plant and that the immune system is strengthened against pathogenic infections through activation of the neutrophils, macrophages, polymorphonuclear leukocytes, and natural killer cells [17].

The aim of the present work was designed to evaluate the combined treatment with MQ and EP in experimental S. mansoni infection in-vivo versus PZQ. Drug evaluation was done parasitologically and histopathologically in addition to studying electron microscopic changes of the adult worms.

 Materials and Methods

Parasites and experimental infection with Schistosoma mansoni

Cercariae of S. mansoni (Egyptian strain) were obtained from infected Biomphalaria alexandrina snails, which were reared and maintained at Schistosome Biological Supply Program, Theodor Bilharz Research Institute, Giza, Egypt. Infection was done by tail immersion technique using freshly shed cercariae in a dose of 70 ± 5 cercariae/mouse according to Liang et al. [18].

This study was conducted on 120 laboratory Swiss albino female mice strain CD1. They were clean from parasitic infection, weighed 20–25 g at the beginning of the experiment, and were of similar age (3–5 weeks). Animals were fed on a standard diet composed of ∼24% proteins, 4% fat, and ∼4.5% fiber [3].

Experimental design

Mice were classified into six groups: group I (control group), which was subdivided into subgroups a, b, c, d, e, f, and g of 10 mice each; group II (PZQ treated) with 10 mice; group III (MQ treated) with 10 mice; group IV (EP treated) with 10 mice; group V (combined treated with PZQ and EP) with 10 mice; and group VI (combined treated with MQ and EP) with 10 mice.

Group I (control groups)

Ia: none infected and untreated (control negative)Ib: infected and untreated (control positive)Ic: none infected and treated with PZQ (drug control 1)Id: none infected and treated with MQ (drug control 2)Ie: none infected and treated with EP (drug control 3)If: none infected and combined treated with PZQ and EPIg: none infected and combined treated with MQ and EP.

Group II (praziquantel treated)

This group was S. mansoni infected and treated with PZQ, where mice were infected and treated with PZQ at a dose of 500 mg/kg given at two equal divided doses for 2 successive days orally at 6 weeks after infection [19].

Group III (mefloquine treated)

This group was S. mansoni infected and treated with MQ, where mice were infected and treated with MQ at a single full dose of 400 mg/kg given once at 6 weeks after infection [5],[20].

Group IV (Echinacea purpurea treated)

This group was S. mansoni infected and treated with EP, where mice were infected and then treated with EP given orally. It was provided as immulant syrup at a dose of 0.125 mg/kg at 6 weeks after infection and daily for 2 weeks [21].

Group V (drug combination)

This group was S. mansoni infected and treated with PZQ and EP. Infected mice were treated with a combination of PZQ, at a dose of 500 mg/kg given at two divided doses for 2 successive days orally at 6 weeks after infection [19], and EP, which was given orally at dose of 0.125 mg/kg at 6 weeks after infection and daily for 2 weeks [21].

Group VI (drug combination)

This group was S. mansoni infected and treated with MQ and EP. Infected mice were treated with a combination of MQ at a single full dose of 400 mg/kg given once at 6 weeks after infection [5],[20] and EP that was given orally at dose of 0.125 mg/kg at 6 weeks after infection and daily for 2 weeks [21].

Drug preparation and dose adjustment


Distocide was obtained from Egyptian International Pharmaceutical Industries Company. Each tablet contains 600 mg. PZQ was administered orally as a suspension after fresh preparation in 2% cremophore EL [19]. The mice were administered at a dose of 500 mg/kg given at two divided doses for 2 successive days at 6 weeks after infection.


Mephaquin, as 250 mg tablets, was kindly provided by Mepha-La Roche (Basel, Switzerland). It was suspended in 7% Tween-80 and 3% alcohol. MQ was administered orally to mice at a single full dose of 400 mg/kg [5],[20].

Echinacea purpura

EP was provided as immulant syrup 120 ml by Arab Company for Pharmaceuticals and Medicinal Plants (Sharkeya, Egypt) for the treatment of infected group at dose of 0.125 mg/kg [21].

Mice of all experimental groups were killed at 8 weeks after infection.

Study of parasitological criteria

S. mansoni worm burden load

Hepatic and portomesenteric vessels were perfused. Following perfusion, numbers and sex of the adult worms (males, females, and couples) were determined. They were counted by either direct visualization or under dissecting microscope [22]. The reduction percentage in worm numbers, after treatment, was calculated according to Tendler et al. [23] to recover worms for subsequent counting.

Tissue egg load

The number of eggs per gram of tissue was estimated by weighing a piece of liver or small intestine, which was then digested and incubated overnight in 5% KOH. The hepatic and intestinal tissue egg loads were determined by multiplying the average number of eggs in each 1 ml sample by the total volume of KOH and then dividing that value by the weight of the sample to yield the number of eggs per gram of tissue [24],[25].

Oogram pattern

After perfusion, the small intestine of each mouse was separated and transferred to a petri dish. Three fragments (each is 1 cm in length) of the small intestine were cut longitudinally, rinsed in saline, and slightly dried on filter paper. Then, the fragments were examined by the low-power microscopy and the percentages of immature, mature, and dead eggs were counted from a total of 100 eggs per each intestinal segment. They were classified according to the categories previously defined by Pellegrino et al. [26]. The mean percentage of each stage/animal and then the mean percentage of each stage/each group of animals were calculated.

Histopathological study

Liver was removed from all mice of all groups, washed by normal saline 0.9, and plotted with filter paper. Liver specimens were fixed at 10% buffered formalin and embedded in paraffin blocks. The prepared 4-μm-thick sections were examined by light microscopy using hematoxylin and eosin stains. Hepatic granuloma morphometries and granuloma diameter measurement were performed by microscopic magnification of ×200 using an ocular micrometer. The mean diameter of each granuloma was calculated by measuring two diameters of the lesion at right angles to each other. The granulomas were counted in five successive fields of each examined slide. The mean number of granulomas of each group was calculated from the mean values of each individual mouse of that group. Only nonconfluent, lobular granulomas containing eggs in their centers were measured [27].

Scanning electron microscopy examination

Scanning electron microscopy (SEM) examination was performed for adult males and females recovered from the study in accordance with Hassan et al. [28], to determine the extent of damage on the surface of treated worms in comparison with the untreated worms.

Adult male worms of S. mansoni perfused from the hepatic and portomesenteric vessels of infected mice were collected in glutaraldehyde buffer solution (25%) as a fixative overnight at 4°C. They were then washed out of any of the fixative by keeping them overnight at 4°C in phosphate buffer and then passed into rising concentrations of alcohol (30, 40, and 50%), each for 15 min, and kept in 70% alcohol until the time of examination. Before examination, they were washed twice for 30 min in 80 and 90% alcohol, correspondingly. The last wash was for one hour in 100% alcohol. Worms were then mounted on stainless steel holders and put in a drier for ∼30 min and then subjected to sputter coat of gold; the different parts of worms were examined using Joel JEM-1200 SEM, provided with a camera fitted to it. Areas in the worms that showed specific changes were examined and photographed, mainly the tubercles on the tegument.

Data analysis

The collected data were collected, tabulated, and statistically analyzed by statistical package for the social sciences (version 20, (SPSS Inc., Chicago, Illinois, USA)). Two types of statistics were done.

Descriptive statistics included percentage, mean, and SD.

Analytical statistics included analysis of variance 'f' test, Kruskal–Wallis test, post-hoc test, and P  value as a test of significance.

P value was considered significant if it was less than 0.05, highly significant if P  value less than 0.001, and nonsignificant if P  more than 0.05.


Parasitological parameters

Effect of tested drugs on worm burden in different treated groups

The results revealed a highly significant reduction (P Effect of tested drugs on the tissue egg load of different groups

There was a highly significant reduction (P Effect of tested drugs on oogram pattern in different groups

Regarding the oogram pattern, [Table 4] demonstrated a highly significant decrease in the percentage of immature and mature eggs and increase in the percentage of dead eggs in all treated groups in comparison with the infected control group (P Effect of tested drugs on the hepatic granulomas number and diameter of different groups

The results showed a highly significant reduction (P Histopathological results

Hepatic granuloma morphometries

Microscopic examination of stained liver sections (hematoxylin and eosin) of infected control nontreated group Ib mice showed typical large fibrocellular granuloma surrounding living ovum including miracidium and surrounded by lymphocytes, eosinophils, polymorphonuclear cells, epithelioid cells, and fibrous tissues [Figure 2]a.{Figure 2}

Treatment with PZQ or MQ alone reduced the size of the granuloma. It was well-demarcated and circumscribed fibrocellular with central intact ovum in PZQ treated group and dead degenerated miracidium in MQ treated group and surrounded by lymphocytes, eosinophils, neutrophils, epithelioid cells, and collagen bundles. In EP, liver sections showed large-sized fibrocellular granuloma with degenerated ova and heavily inflammatory cells (lymphocytes, eosinophils, epithelioid cells, and collagen bundles) [Figure 2]b, [Figure 2]c, [Figure 2]d. In combined treated mice in groups V and VI, liver section showed marked reduction in the size of the granuloma; they were well defined, surrounding either living or dead egg with few inflammatory cells scattered in between lymphocytes. However, with group VI treatment, liver sections showed restoration of the normal liver architecture, sparsely scattered inflammatory cells with normal central vein and hepatocytes [Figure 2]e and [Figure 2]f.

Results of scanning electron microscopic observations

SEM revealed that the tegument of adult male worm recovered from control nontreated group showed numerous large tubercles with numerous intact spines on the top of tubercles [Figure 3]a, and tegumental surface of untreated S. mansoni females showed normal surface with intact spines [Figure 3]b. The extracted adult worms from PZQ treated group showed alteration of tegument, loss of intertubercular ridges, and surface blebbing [Figure 3]c. The tegumental surface of treated adult S. mansoni males with MQ showed loss of intertubercular ridges, loss of spines, severe corrugation, and extensive blebbing, whereas female worm showed furrowing, loss of spines, poring, fissuring, and cracking of its surface [Figure 3]d and [Figure 4]a. In group treated with EP (group IV), the tegumental surface of adult males showed flattening of tubercles, loss of spines, loss of intertubercular ridges, extensive blebbing, and starting of the sloughing of the tegument [Figure 4]b. In combined treatment (PZQ and EP), the tegumental changes were marked, severe, and progressive in the form of distortion of tubercles, blebbing, loss of spines, swelling of the surface, and loss of intertubercular ridges. In the same manner, MQ and EP treated group showed more advanced changes, including poring, cracking, furrowing, and sloughing [Figure 4]c and [Figure 4]d.{Figure 3}{Figure 4}


Schistosomiasis is a neglected tropical disease, endemic in 76 countries, that affects more than 240 million people [29]. Schistosomiasis chemotherapy depends on a single drug, PZQ, which was employed for treatment of infections caused by all Schistosoma spp. [30]. So, there is an urgent need to develop a new antischistosomal drug. New research has shown that MQ exhibits antischistosomal properties [5],[8]. This was reported for S. mansoni [31] and S. japonicum [32].

PZQ given at a dose of 500 mg/kg caused pronounced significant curative effects where the mean number of adult male, female, couples, and total worms was 67.64, 57.14, 66.42, and 68.44%, respectively (P [33] and El-Lakkany et al. [34] who have documented that PZQ at a dose of 500 and 1000 mg/kg at 6 weeks after infection caused a reduction in the total numbers of males by 82.6 and 96.6%, respectively. This difference could be attributed to different drug dose.

The results of the current study revealed that MQ given at dose of 400 mg/kg achieved a significant reduction in the number of perfused adult male, female, couple, and total worms (76.47, 80, 82.14, and 88.08%, respectively) (P [35] who reported that MQ given at a single oral dose of 200 mg/kg for treatment of S. haematobium-infected hamsters 49 days after infection resulted in considerable worm burden reductions of 75.9, 69.6, and 88.6% for male, female, and coupled worms, respectively. On the contrary, Abdel-Fattah and Ahmed [33] reported that MQ monotherapy in its full dose (400 mg/kg) at 6 weeks after infection eradicated adult male and female worms (100%). The deaths of the Schistosoma worms could be attributed to the metabolic disorders, mechanical destruction, and muscular contraction of the treated worms [36].

The results of the present study demonstrated that oral administration of EP or its combination with MQ or PZQ to infected mice was significantly effective in reducing worm burden and egg count, indicating their effective antischistosomal action. EP at a dose of 0.125 mg/kg caused a significant reduction in the mean numbers of male, female, couple, and total worms (41.17, 42.85, 41.07, and 40.64%, respectively). To our knowledge, this is the first report to investigate the therapeutic effects of EP on S. mansoni in experimentally infected mice either alone or in combination with PZQ and MQ.

In consonance, Canlas et al. [37] reported the effect of Echinacea on trypanosomatid parasite. The results showed slowed or eliminated motility and rounding of both Leishmania donovani and Trypanosoma brucei at high concentrations and explained that the anti-inflammatory effect of Echinacea negatively affects proliferation by killing the parasites which could be explained either by stimulation of apoptosis or necrosis and/or through growth inhibition. The antischistosomal effect of EP may be attributed to its antioxidant activity that enhances the immunity of the host to attack the parasite and thereby reduce infection and morbidity and protect the mice from pathogens to a certain level [38].

Concerning the tissue egg load, the highest reduction rate was obtained by combined MQ and EP (93 and 89% for liver and intestine, respectively). Moreover, MQ and combined PZQ and EP showed significant reduction in tissue egg load (88 and 87%, respectively, for intestine and 86 and 81%, respectively, for liver) (P P et al. [39], who stated that administration of MQ at a dose of 400 mg/kg at day 35 after infection caused significant reduction in tissue egg loads in intestine and liver by 93.9 and 94.3%, respectively. The reduction of the tissue egg load was attributed to the reduction that occurred in the worm load. Moreover, Botros et al. [40]found that PZQ reduced the hepatic and intestinal tissue egg loads significantly by 60 and 90%, respectively.

In contrary to our results, Selem and Eraky [35] reported that the effect of MQ treatment 82 days after infection revealed an insignificant egg load reduction rate in the liver (41.6%) and intestine (29%).

The results of the current work revealed that administration of EP caused significant reduction in the tissue egg load of intestine by 35% and liver by 46% (P P [36] that showed decrease of immature eggs (30.8 ± 7.8) and increase of dead eggs (8.4 ± 2.2) and mature eggs (40.6 ± 10.2) compared with infected untreated hamsters (53.3 ± 0.9, 10 ± 1.2, and 36.7 ± 0.9 for immature, dead, and mature eggs, respectively). All these results were statistically insignificant (P > 0.05). This discrepancy could be easily attributed to species (S. haematobium), female sex-related different susceptibilities, and potential host-specific response (mice vs. hamster).

Although more reduction rate was reported by Fahmy et al. [39], they concluded that administration of MQ at a dose of 400 mg/kg at day 35 after infection caused complete disappearance of all immature and mature ova.

Administration of PZQ resulted in highly significant reduction in immature (25.10 ± 2.02) and mature (39.8 ± 6.56) stages of eggs with subsequently an increase in the number of dead eggs (35.1 ± 5.95) (P et al. [41], who reported that the egg reduction rate was 68.2% following administration of PZQ at a single dose of 40 mg/kg.

The results revealed that EP treatment showed significant reduction in immature (30.90 ± 3.57) and mature (20.60 ± 4.47) stages of eggs with subsequently an increase in the number of dead eggs (48.50 ± 6.31) (P [42].

Regarding the histopathological results, there was a highly significant difference recorded between S. mansoni-infected mice treated with MQ and infected control with reduction of hepatic granulomas diameter by 69% and numbers by 71% (P P [33] who reported that the histopathological examination of liver sections of mice treated with MQ containing regimens showed no schistosomal granulomas, and only mild portal tract infiltration was seen, whereas in PZQ monotherapy, granulomas were of cellular nature and significantly less in number. The reduction rate of the granuloma number was 90%; however, the reduction rate in the mean granuloma size was 53% (P [43].

In the current study, examination of hepatic sections obtained from EP treated group showed that there was a significant reduction of the hepatic granulomas diameter by 48% and numbers by 29% in comparison with control group (P P P [42]. EP extract stimulates the phagocytic activity of the reticuloendothelial system [17].

Regarding SEM results, the current work observed that schistosomes recovered from treated mice with PZQ showed variable degree of tegumental damage in the form of loss of intertubercular ridges with surface blebbing and vesicles formation associated with rupture of many tubercles and vaculation with flattening of spines. These results were in agreements with Deribew and Petros [44], who documented that PZQ caused a disruption of the worm's outer surface after exposure.

Tegumental alterations observed were in the form of loss of intertubercular ridges, loss of spines, severe corrugation, and furrowing in male, whereas in female, poring and cracking of the surface in addition to blebbing were seen in adult schistosomes recovered in MQ treated group. These results were similar to that reported by Manneck et al. [45]. They reported a single oral dose of MQ (400 mg/kg) to S. mansoni-infected mice caused localized blebbing on the tegument appeared after one day and became more severe 3 days after treatment, particularly in female worms. Recent study was performed to evaluate the in-vivo effect of MQ on S. haematobium-infected hamster. The tegument was swollen in some parts and flattened in other parts with loss of the tubercles, shrinking, scattered blebbing, and furrowing. MQ effect on schistosome's tegument was more prominent in treated adults than in juvenile worm [35]. Manneck et al. [45] documented shrinkage and swelling of the tegument in female worms, and numerous blebbing and loss of spines, fissuring, and pores were also seen. Moreover, Selem and Eraky [46] observed different tegumental changes including flattened spines, shrinking, corrugation, unfolding, and widening of gynecophoric canal with extensive sloughing and disintegration of the tegument.

Regarding the antischistosomal effects of EP, the tegumental changes observed from adult schistosomes showed variable degree of damage in the form of flattening of tubercles, loss of spines, loss of intertubercular ridges, blebbing, and sloughing of the tegument. Similar effects were recorded in Trypanosoma and Leishmania parasites, and these effects were attributed to the anti-inflammatory effect of Echinacea, which negatively affects the proliferation by killing the parasites, which could be explained either by stimulation of apoptosis or necrosis [37].

The schistosomicidal action of PZQ could be explained by that, the damage caused to Schistosoma tegument may lower the ability of S. mansoni to evade the immune response by increasing the exposure of parasite antigens at the worm surface and disrupting the parasite masking coat of host antigen [47]. This mechanism of action could be applied also on EP which resulted in pronounced tegumental damage allowing the host immune response to kill the parasite.

In conclusion, MQ treatment had effective schistosomicidal properties through reduction of worm burden and tissue egg load. Moreover, MQ largely alleviated schistosomal hepatic pathology. In addition, it clearly reduces the liver granuloma size with some degree of improvement in the status of the liver. So, MQ is a promising treatment that could be used for development of new anti-Schistosoma drugs. Furthermore, the present findings proved that EP extract showed promising antischistosomal properties presented by its therapeutic effect on the parasitological parameters of the S. mansoni-infected mice especially with combination with MQ. It is recommended to perform further studies to examine the exact mechanism of action of EP on S. mansoni and to study its effect on other parasitic infections.

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Conflicts of interest

There are no conflicts of interest.


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