*cruzi* [39–42], *Acanthamoeba castellanii* [43], *Leishmania* spp. [42, 44–46], and *Plasmodium* [47].

In the case of helminth parasites, this compound has been tested against *S. mansoni*. Porto *et al.,* (2021), by electron microscopy analysis, reported that amiodarone affects the viability of schistosomes *in vitro* with effective concentrations of 50% and 90% values ranging from 8 to 50 μM. Also, amiodarone was tested in a murine model of schistosomiasis for both early and chronic *S. mansoni* infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. They report that Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, this compound caused a significant reduction in worm and egg burden in early infection (>50%) [48]. Similarly, Talaam *et al.*, (2021), evaluated the possible effect of amiodarone against *S. mansoni*. In this experiment, amiodarone showed complete inhibition of cercaria motility after 18 hours. In the case of schistosomula, after 24 hours with amiodarone, the inhibition of motility was complete. In adult parasites, amiodarone inhibited the motility after 20 hours of incubation was not complete, providing mean motility scores of 0.3 and 1.0 for the male and female, respectively [49]. In *in vivo* experiments, mice were prophylactically treated with amiodarone (50 mg/kg) by 4 days of once-daily intraperitoneal injection, starting 1 day prior to infection, and then euthanized six days postinfection to recover the schistosomula from the lungs. The results show a worm burden reduced to 14.7%. In the case of therapeutic treatment, the mice at week six after infection were treated intraperitoneally with amiodarone (50 mg/kg) for 4 days, and subsequently, they were sacrificed 14 days after the last treatment, the parasite load showed a decrease to 29.2% [49].

### **3.5 Paclitaxel**

Paclitaxel (Taxol) is a drug used in the treatment of breast, ovarian, lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers. It has also been used in Kaposi's sarcoma.

The use of this drug against helminths has been little tested. Pensel *et al.,* (2014), tested the *in vitro* effect of this compound against germinal cells, protoscoleces and cysts of *Echinococcus granulosus*, and parasites responsible for echinococcosis in humans. They report that the use of paclitaxel at a concentration of 1, 5, and 10 μg/ ml inhibited the growth of *Echinococcus granulosus* cells in a time-dependent manner. In addition, paclitaxel had a direct effect against protoscoleces in a dose- and time-dependent manner. At 30 days postexposure with 10 and 5 μg/ml paclitaxel, viability of protoscoleces decreased to approximately 60% and the treatment with 1 μg/ml also showed protoscolicidal effect, with 75.3% of parasites remaining viable in culture. Finally, in an *in vitro* cyst incubation it was shown that paclitaxel resulted in dramatic alterations within 3 to 5 days after initiation of treatment [50]. In another experiment, Huang *et al.* (2018) evaluated the effect of paclitaxel on growth and proliferation of *Echinococcus multilocularis* metacestodes. They exposed metacestode tissues *in vitro* to paclitaxel (2, 5, and 10 μM) for one week and, thereafter, were injected into the peritoneum of *Meriones unguiculatus*. After, magnetic resonance imaging and simultaneous positron emission tomography were applied to monitor *in vivo* growth of drug-exposed *Echinococcus multilocularis*. The *in vivo* growth of metacestodes was suppressed until 3 months postinfection, thereafter, parasite tissues enlarged up to 3 cm3 [51].

#### **3.6 Docetaxel**

Docetaxel (taxotere) is a chemotherapeutic drug administered as a treatment for some types of cancer, such as breast, prostate, and non-small cell lung cancer, but it also may be used for many other types of cancers.

The only report where the effect of docetaxel against a helminth has been evaluated was carried out by Huang *et al.* (2018). They report that at three months postinfection, docetaxel (at 10 μM, 5 μM and 2 μM) inhibited *in vivo* growth and proliferation of *Echinococcus multilocularis*, and at 5 months postinfection, only in the 2 μM docetaxel exposure group 0.3 cm3 of parasite tissue was found [51]. Moreover, in *Meriones* infected with *Echinococcus multilocularis* metacestodes previously exposed to docetaxel, *in vivo* grown parasite tissues weighed 0.2 g and *in vitro* cultured *Echinococcus multilocularis* metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post-drug exposure. With the above, they suggest that the use of this drug can work as an alternative option for the treatment of alveolar echinococcosis [51].

#### **3.7 Cisplatin**

Cisplatin is a first-generation platinum-containing drug, used in the treatment of various solid tumors. This drug prevents or inhibits cell maturation and proliferation.

The effect of cisplatin against helminths was tested by Eldeed *et al.,* (2018), in an *in vivo* and *in vitro* experiments where they tested a single dose of cisplatin against *S. mansoni*. In *in vitro* experiments, they report that a single dose of cisplatin (10 to 200 μg/ml) for 24 or 48 hours demonstrated as reduction in viability of the treated worms after 24 hours and, especially, after 48 hours. Moreover, the survival rate of the treated worms decreased gradually in a concentration-dependent manner [52]. On the other hand, in *in vivo* experiments in which female mice were injected subcutaneously with cercariae *of S. mansoni* and administered cisplatin at a dose of 8 mg/kg/day for 3 days beginning on day 42 postinfection, to which samples were collected 2 weeks after the last dose of treatment, they reported that cisplatin significantly reduced the number of living ova, while the number of dead eggs significantly increased. Furthermore, the number of worms recovered was less compared to the control group [52]. The examination for the tegument of adult male *S. mansoni* recovered from infected mice showed erosion, necrosis, and severe damage to the tegument surface, abnormal dropped spines from the tegument surface, vacuolization of the subtegumental cells, and disorganization of muscle layers after treatment with cisplatin [52]. Finally, hepatic histological analysis of *S. mansoni*-infected mice shows that cisplatin treatment decrease granuloma size. In liver function tests, alanine aminotransferase was decreased in infected animals treated with cisplatin compared to their infection control [52].

#### **3.8 Natural products**

Recently, the use of phytoestrogens with antiparasitic activity has increased. One of them, genistein, an isoflavone isolated from soybean, exhibits significant metacestodicidal activity *in vitro,* but also binds to the ER and induces estrogenic effects. Furthermore, synthetic genistein derivatives have shown an improved metacestodicidal effect [53].

#### *New Uses for Old Drugs and Their Application in Helminthology DOI: http://dx.doi.org/10.5772/intechopen.106176*

Parasitic diseases remain a major public health problem affecting hundreds of millions of people, particularly in tropical developing countries. The limited availability and affordability of pharmaceutical medicines mean that the majority of the world's population depends on traditional medical remedies, and it is estimated that some 20,000 species of higher plants are used clinically throughout the world [54]. In medieval times, plants with reputed antihelminthic properties were often mixed with mineral salts (arsenic, copper, etc.) or more esoteric materials (blood, feces, fluids from reptiles, wild animals, etc.) to form quite bizarre and often hazardous concoctions – for both parasites and hosts alike. With time, trial, and error, such preparations were refined in an attempt to at least moderate the undesirable consequences to the host, but with the advent of safer and more effective synthetic antihelminthic compounds, they rapidly disappeared from the veterinary antihelminthic market. Nevertheless, it is of interest to note that the WHO has recently estimated that 80% of the population of developing countries rely on traditional medicine, mostly plant drugs, for their primary health care needs. Higher plants represent a rich source of new molecules with pharmacological properties, which are lead compounds for the development of new drugs. During the last decades, the renewed interest in researching natural products has led to the introduction of several important drugs, such as the anticancer drugs vinblastine and taxol or the antimalarial agent artemisinin. Success in natural products research is conditioned by careful plant selection, based on various criteria such as chemotaxonomic data, information from traditional medicine, field observation, or even random collection. One main strategy in the isolation of new lead compounds consists of so-called bioactivity-guided isolation, in which pharmacological or biological assays are used to target the isolation of bioactive compounds. One major drawback of this strategy is the frequent isolation of known metabolites. The tropical fruit *Carica papaya* and its seeds have proven antihelminthic and anti-amoebic activities [55]. To determine the effectiveness of air-dried *C. papaya* seeds on human intestinal parasitosis, 60 asymptomatic Nigerian children with stool microscopic evidence of intestinal parasites received immediate doses (20 mL) of either an elixir composed of air-dried C. papaya seeds and honey (CPH) or honey alone (placebo) in two randomized treatment groups. Repeat stool microscopic examinations were conducted 7 days post-intervention for intestinal parasites. Significantly more subjects given CPH elixir than those given honey had their stools cleared of parasites [23 of 30 (76.7%) vs. five of 30 (16.7%); z = 4.40, P = .0000109]. There were no harmful effects. The stool clearance rate for the various types of parasites encountered was between 71.4% and 100% following CPH elixir treatment compared with 0−15.4% with honey. Thus, air-dried C. papaya seeds are efficacious in treating human intestinal parasites and without significant side effects. Their consumption offers a cheap, natural, harmless, readily available monotherapy, and preventive strategy against intestinal parasitosis, especially in tropical communities. Further and large-scale intervention studies to compare *C. papaya* with standard antiparasitic preparations are desirable [55]. For example, schistosomiasis, a widespread helminthic disease whose treatment is chemotherapy based, the drug of choice being praziquantel. Since resistance to praziquantel has been discovered in the exposed parasites, alternative drugs must be considered. Myrrh is an oleo-gum resin from the stem of the plant *Commiphora molmol* [56]. This study was performed on 204 patients with schistosomiasis. The drug was administered at a dose of 10 mg/ kg of body weight/day for three days, inducing a cure rate of 91.7%. Re-treatment of cases who did not respond with a dose of 10 mg/kg of body weight/day for six days

gave a cure rate of 76.5%, increasing the overall cure rate to 98.09%. The drug was well tolerated, and side effects were mild and transient. Twenty cases provided biopsy samples six months after treatment and none of them showed living ova [56]. Other treatments involve hand infusions and decoctions of the leaves, roots, and inflorescences of the herbaceous shrub *Chenopodium ambrosioides* (American wormseed, goosefoot, epazote, paico); additional related species, indigenous to the New World, have been used for centuries as dietary condiments and as traditional antihelminthics by native peoples in the treatment of intestinal worms [57]. Commercial preparations of *Chenopodium* oil and its active constituent, ascaridol, obtained by steam distillation, have been and continue to be used with considerable success in mass treatment campaigns. Ethnopharmacological studies in a community of Mayan subsistence farmers in Chiapas, Mexico, confirmed that decoctions containing up to 300 mg of dry plant material (kg/body weight) were widely used and traditionally highly regarded in the treatment of ascariasis. However, therapeutic doses of up to 6000 mg (kg/body weight) of powdered, dried plant material had no significant antihelminthic effect on the adults of *Necator, Trichuris,* or *Ascaris*. Gas-liquid chromatographic analyses of plant samples used consistently demonstrated the presence of ascaridol in the expected amounts. Possible origins of subjective belief in the efficacy of *C. ambrosioides* may be related to the positive association of spontaneous or peristalsis-induced passage of senescent worms immediately following a therapeutic episode [57]. It is also possible that, in the past, varieties of the plant containing much more ascaridol were used. The results of these controlled field studies did not sustain any widely held traditional beliefs nor did they support the value of the therapeutic practices regarding this plant. It is, therefore, essential that all indigenous ethnomedical practices be objectively evaluated for efficacy and safety using the appropriate protocols before being considered for their adaptation or promotion in health care programs [57].

Naphthoquinones are naphthalene-derived compounds that can be found in some plants. These products possess antibacterial, antifungal, antitumoral, and antiparasitic properties. Aranda-López *et al.,* (2021), evaluated *in vitro* anti-helminth effect of a pure naphthoquinone (naphthoquinone 4a) in a model of murine cysticercosis caused by *Taenia crassiceps*. Naphthoquinone 4a causes paralysis in the cysticerci membrane from day 3 of the in vitro treatment. Moreover, it induces changes in the shape, size, and appearance of the cysticerci and a decrease in the reproduction rate depending on the duration of the treatment and the concentration of the compound [58]. Wang *et al.,* (2017), evaluated the effect of 1,4 naphthoquinone against *Caenorhabditis elegans* nematodes and eggs and report that 1,4 naphthoquinone kills more than 50% of nematodes and inhibits more than 50% of eggs hatching at a dose of 50 μg/ml. This effect is mediated by stimulating oxidative stress (increase reactive oxygen production, superoxide dismutase activity, and the heat-shock transcription factor (HSF)-1 pathway). In addition, they showed that the lethality caused by naphthoquinone was related to the Insulin/IGF signaling (IIS) pathway, and the effect on IIS pathway-related genes (*age-1, sod-3, mtl-1, ctl-2, daf-12*) indicated that 1,4-naphthoquinone could activate this pathway and suppress the expression of DAF-16 target genes [59]. El-Beshbishi *et al.,* (2019), in an *in vitro* study tested the use of artemisinin-naphthoquinone phosphate combination against *Schistosoma haematobium* and its vector *Bulinus truncates*. They report that naphthoquinone treatment at a dose of 1 μg/ml of *Schistosoma haematobium* worms for 24 hours reduces worm motility, while the dose of 20 μg/ml results in 25–100% mortality of adult flukes within 48–72 hours. Moreover, the incubation of miracidia and cercaria with artemisinin-naphthoquinone phosphate at a concentration of 7.5 μg/ml killed all the free larval stages within 40 and

#### *New Uses for Old Drugs and Their Application in Helminthology DOI: http://dx.doi.org/10.5772/intechopen.106176*

15 min, respectively. Finally, the exposure of *Bulinus truncatus* adult snails to 20 ppm of the combined regimen caused a mortality rate of 100% within 24 hours [60]. In an experiment realized by Cha *et al.,* (2019), where they evaluated the nematicidal activity of three naphthoquinones (1,4-naphthoquinone, juglone, and plumbagin) against the pine wood nematode (*Bursaphelenchus xylophilus*), showed that lethal concentration 50 (LC50) at 48 hours of exposure was 100 ppm for 1,4 naphthoquinone, 57 ppm for juglone, and 104 ppm for plumbagin. In *in vivo* test, they report that mortality of *Bursaphelenchus xylophilus* was significantly affected by the presence of the three naphthoquinones at concentrations above 62.5 ppm. In the semi-*in vivo* assay, the population of inoculated *Bursaphelenchus xylophilus* was significantly decreased at two weeks after treatment with juglone when compared with the effects of treatment with 1,4-naphthoquinone and plumbagin. The mechanism by which mortality occurs was associated with the generation of reactive oxygen species by naphthoquinones that cause oxidative stress in the parasite [61]. Rufener *et al.,* (2018), tried *in vitro* and *in vivo* buparvaquone (a second-generation naphthoquinone with action on hemoprotozoa) against *Echinococcus multilocularis*. Their results show that buparvaquone has an Inhibitory Concentration 50 (IC50) of 2.87 μM against *in vitro* cultured *Echinococcus multilocularis* metacestodes. Moreover, transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on, and additional tests showed that had a reduced activity under anaerobic conditions. Furthermore, buparvaquone show an inhibition effect of the cytochrome bc1 complex in *Echinococcus multilocularis* germinal layer cells. On the other hand, in a *in vivo* experiment using mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), the treatment failed to reduce the parasite burden [62].
