**Abstract**

Parasitic infection research, performed on both humans and domestic animals, has been mostly focused on vaccines, diagnostic methods, epidemiology, and the evolutionary origins of parasites, thanks to the emergence of genomics and proteomics. However, the basic biology of the host-parasite interactions of several medical or veterinary important parasites has not been fully studied. Limited information has been obtained on the intricate neuroimmunoendocrine effects of host-parasite interplay in particular; therefore, the consequences of these interactions, and their possible therapeutic applications, are in need of thorough research. The current manuscript attempts to review the available literature regarding the host-parasite neuroimmunoendocrine network and to discuss how this basic research can be used to design new treatments using hormones, antihormones, and hormone analogs as a novel therapy against parasitic diseases. In addition, these studies may also contribute in identifying alternative treatments for parasitic diseases in the future. The complex immune-endocrine network may also help in explaining the frequently conflicting results observed in infections with regards to host sex and age and offer helpful insight into other research avenues besides parasite treatment and control strategies. Finally, several natural products isolated from plants, used in traditional medicine, offer an alternative approach for natural products in the preparation of inexpensive and effective antiparasitic drugs.

**Keywords:** drugs, parasitic diseases, parasitology, parasite, parasite infection treatment

## **1. Introduction**

Parasitic infections rank amongst the most significant causes of morbidity and mortality in the world, yet economic and other factors have contributed to a lack of innovation in treating these diseases. Nitazoxanide (NTZ), a pyruvate ferredoxin oxidoreductase inhibitor, is a new antiparasitic drug notable for its activity in treating common intestinal helminths. The availability of a product with this spectrum of activity raises interesting new possibilities for treating intestinal parasitic infections [1]. Recent studies have shown that NTZ inhibits pyruvate ferredoxin oxidoreductase (PFOR), a vital enzyme of central intermediary metabolism in protozoan. In contrast to the nitroimidazoles, NTZ appears to interact directly with PFOR (i.e., NTZ is not

dependent on reduced ferredoxin), and the products of NTZ activation do not induce mutations in DNA. This distinct mechanism of action is important in explaining the therapeutic efficacy of this drug against organisms displaying high level of resistance to metronidazole [2].

The use of hormones, or hormone antagonists, as immunoregulators or as agents to prevent colonization, growth, or reproduction of parasites, may be potentially useful in the treatment of a large variety of parasitic diseases, particularly those in which hormones are known to have a strong controlling effect. The discovery of new antiparasitic drugs is a very expensive process that has resulted in few drugs being commercialized over an extended period of time (**Figure 1**).

Since new drugs must be targeted against parasite survival interactions and be selective and unimpaired by known resistance mechanisms, the knowledge gained by studying physiological regulation of the host-parasite interaction could make it less expensive and faster, to produce antiparasitic drugs. Recent advances in genomic technology offer us the opportunity to identify, validate, and develop constructs of parasite key molecules that could be regulated by hormones, for testing drugs such as tamoxifen, RU-486, fadrozole, or flutamide (all of them hormone agonists) that could result in the identification of antiparasitic drug targets. This would also give new uses to old drugs that are already on the market. Understanding how the host's neuroimmunoendocrine system can, under certain circumstances, favor the colonization of a parasite and how the characterization of the parasite's hormone receptors involved might assist the design of hormonal analogs and drugs that affect the parasite exclusively [3]. Most of the current research on parasitic infections that affect humans and domestic animals has been focused on vaccines, diagnostic methods, epidemiology, new drug design, and recently, with the advancement of genomics and proteomics, on the evolutionary origins of parasites. However, the design of new treatments using hormones, antihormones, and hormone analogs as a possible novel therapy during parasitic diseases has been recently proposed. The pharmaceutical industry is now currently investing a higher sum of resources in the development of new antiparasitic

#### **Figure 1.**

*The cost and time of the drug development process. It does start with targeting the disease. Then it goes throughout the basic research until it gets the lead compound. If there is a failure, and the compound is not promissory, then it goes back. Then the process continues until a marketable drug is obtained. The accumulated cost is around 300 million dollars to get to the final product. Today, these costs are being greatly decreased. The time since the basic compound is found in the marketable drug is around 20 years. However, it may be more if there are failures in the development of the same. In the case of helminthology, few compounds are being discovered since praziquantel, mebendazole, and albendazole were discovered.*

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

drugs. We and other research groups (focusing mainly on sex-associated susceptibility to infection, the direct effects of adrenal and sex steroids as well as the study of parasite genomes) have suggested the study of known drugs, whose formulae have been redesigned, to test possible antiparasitic function. In this respect, animal models are highly convenient in the study of infectious diseases and the design and test of new drugs. It is desirable that these drugs are also tested in *in vitro* systems, where parasite growth, reproduction, and viability can be evaluated in response to pharmacological treatment [3]. An *in vitro* approach is convenient when seeking to define the molecular mechanisms by which a drug affects a parasite without including hostparasite interaction parameters (**Figure 2**).

In the present manuscript, we highlight the novel use of known drugs (currently used in cancer treatment and other proliferative disorders) to treat parasitic infections, i.e., cysticercosis, trichinellosis, ascariasis, schistosomiasis, toxocariasis, onchocerciasis, and others helminthic infections. Parasite fecundity is extremely important in the biological course of infection, therefore, it is worth considering some of the well-described antiproliferative drugs, which may also have inhibitory effects upon parasite reproduction, even if pathogens are inside the host cell. The genome of several parasites is currently being sequenced, which enables the knowledge acquisition on the molecular mechanisms involved in the infectious process, as well as in the design of different transcriptome maps, that could potentially explain the interaction and expression of the involved genes in parasite colonization and reproduction [3]. Hormonal effects are the keystone for parasite development. Experimental evidence, previously obtained by our group, suggests that the scolex evagination of *Taenia solium* cysticerci is stimulated by progesterone, however, other authors refer to the opposite effect for progesterone, which inhibits the reproduction and parasite molting in *Trichinella spiralis* [4, 5]. The target genes for progesterone action remain to be identified, and we must wonder if commercial progestin would inhibit parasite reproduction and differentiation. Although the knowledge of host-parasite interactions has grown over the last few years, there are still many unanswered questions that would allow us to fully unravel these host-parasite events and consider the complex neuroimmunoendocrine network involved in this pathogenic relationship. With this in mind, it is important to understand the biological role of sex steroids and the use of their inhibitors, alongside other drugs, aimed to inhibit cellular proliferation in the parasite. An experimental approach could clarify these points and further contribute

#### **Figure 2.**

*The current drug discovery process specifically in helminthology. In this case, we focus on proteases as an example. But it is only the step of finding the lead compound. It can take up to 3 years to find the lead compound, and up to 2 million dollars to obtain it. Then, it has to go throughout all the further steps pointed out in* **Figure 1***.*

to elucidating the host's biological factors that control, or facilitate infection. Research on drugs utilized to treat different diseases could well allow the discovery of their active role in the regulation of parasite gene transcription during proliferation. Only a few novel classes of antiparasitic drugs have emerged over the last few decades thus reflecting the difficulties associated with bringing a safe and effective molecule to the market. Moreover, the screening paradigm has shifted from an empirical whole parasite screening to mechanism-based high-throughput screening. This approach requires a heavy investment in molecular parasitology and in depth understanding of the basic biology of parasites, as well as considerable infrastructure for the screening assays. Add to this the fact that the drug discovery process is interactive with high attrition, and the animal health industry, by necessity, must focus on discovering medicines for diseases that will provide a profit in return. In this regard, the rapid progression of genomics has unlocked a plethora of tools dedicated to target identification, validation, and screening, resulting in revolutionizing mechanism-based screening methods for antiparasitic drug discovery [3]. Therefore, the use of sexual hormones, their analogs, and other immune-regulatory factors are receiving more attention concerning new therapeutic strategies in the prevention and outcome of parasitic diseases. As an example, the treatment with testosterone or dihydrotestosterone in a model of murine cysticercosis, prior to infection, reduced the parasite load by 50% and 70%, respectively. This effect was mediated by significant lymphocyte proliferation recovery and enhanced IL-2 and IFN-γ production in the infected mice [6], suggesting the possible use of androgens to activate the host's immune system and increase resistance against lethal infections [7]. Estrogens and progestins, particularly estradiol and progesterone, contribute to either susceptibility or resistance to parasitic disease during pregnancy [8]. Usually, these sexual hormones are associated with immunosuppression leading to susceptibility to infection, as demonstrated in the murine cysticercosis model [9, 10]. However, parasiticidal activity was observed in murine trichinellosis. *In vitro* and *in vivo* experiments performed on *Trichinella spiralis* newborn larvae (NBL) in pregnant rats showed that progesterone can induce activation of peritoneal cells to destroy NBL in an antibody-independent manner. This observation opened up the possibility for the use of progesterone to treat trichinellosis but not cysticercosis [11, 12]. Sexual hormone precursors, analogs, antagonists, or inhibitors can also be used to modify the immune response induced by specific parasites to affect the outcome of infection. For example, exogenous administration of dehydroepiandrosterone confers resistance to several intracellular metazoan and protozoan parasites [13–15]. Concerning *Taenia crassiceps* in specific, this effect is not mediated through over induction of the Th1 response. Instead, the antiparasitic effect of dehydroepiandrosterone targets the reproduction, growth, viability, and infectivity of the parasite [16]. Regarding sexual steroid analogs, the synthetic androstane steroid 16α-bromoepiandrosterone (HE2000) has shown positive immune effects in experimental infection as malaria and tuberculosis, even infection with human immunodeficiency virus [17], due to its anti-inflammatory properties and the induction of innate and adaptive cellular immunity [13, 17–19].

In other studies, the inhibition of sexual hormones induced the recovery of a specific cellular immune response. Recently, the use of phytoestrogens as antiparasitic drugs has increased. Genistein, an isoflavone isolated from soybean, exhibits significant metacestodicidal activity *in vitro* but also binds to the ER and induces estrogenic effects. Furthermore, modified synthetic genistein derivatives have shown improved metacestodicidal activity [20].
