Schistosomiasis control: praziquantel forever?

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Molecular & Biochemical Parasitology 195 (2014) 23–29

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Molecular & Biochemical Parasitology

Review

Schistosomiasis control: praziquantel forever? Donato Cioli ∗ , Livia Pica-Mattoccia, Annalisa Basso, Alessandra Guidi Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy

a r t i c l e

i n f o

Article history: Received 8 April 2014 Received in revised form 7 June 2014 Accepted 13 June 2014 Available online 21 June 2014 Keywords: Schistosomiasis Praziquantel Oxamniquine Drugs Resistance Mechanism of action

a b s t r a c t Since no vaccine exists against schistosomiasis and the molluscs acting as intermediate hosts are not easy to attack, chemotherapy is the main approach for schistosomiasis control. Praziquantel is currently the only available antischistosomal drug and it is distributed mainly through mass administration programs to millions of people every year. A number of positive features make praziquantel an excellent drug, especially with regard to safety, efficacy, cost and ease of distribution. A major flaw is its lack of efficacy against the immature stages of the parasite. In view of its massive and repeated use on large numbers of individuals, the development of drug resistance is a much feared possibility. The mechanism of action of praziquantel is still unclear, a fact that does not favor the development of derivatives or alternatives. A large number of compounds have been tested as potential antischistosomal agents. Some of them are promising, but none so far represents a suitable substitute or adjunct to praziquantel. The research of new antischistosomal compounds is an imperative and urgent matter. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

5.

6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molluscicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enter praziquantel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Operational convenience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. PZQ resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Mechanism of action of PZQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Summary considerations on PZQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. PZQ derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Oxamniquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antimalarial drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Furoxan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bioinformatics and high throughput screenings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: IBCN-CNR, Via Ramarini 32, 00015 Monterotondo (RM), Italy. Tel.: +39 9009 1355; fax: +39 06 9009 1288. E-mail addresses: [email protected] (D. Cioli), [email protected] (L. Pica-Mattoccia), [email protected] (A. Basso), [email protected] (A. Guidi). http://dx.doi.org/10.1016/j.molbiopara.2014.06.002 0166-6851/© 2014 Elsevier B.V. All rights reserved.

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1. Introduction For countless centuries, schistosomiasis has been, and still is, a serious scourge for people living in tropical and sub-tropical areas of the world [1]. Estimates of the total number of currently infected people are usually around 200 million, ranging from 193 [2] to 207 [3] million, while the number of people at risk of infection has been calculated to be between 600 and 779 million [2,3]. The development of water resources in several tropical countries has probably contributed to maintain these figures at relatively constant – if not increasing – levels in recent years [3]. Mortality has been estimated at 280,000 deaths/year in Sub-Saharan Africa [4], while the overall level of disability caused by schistosomiasis has been recently re-evaluated and extended to include previously neglected effects of chronic infection like anemia, growth stunting and diminished physical and mental fitness [5]. It is customary to summarize the situation by saying that, among parasitic diseases, schistosomiasis ranks second after malaria for the number of people infected and for its health impact. Such being the general picture of the disease, the immediate connection that comes to mind of anyone considering possible tools for its control, is undoubtedly the word “praziquantel” (PZQ). Indeed, this drug is used today so extensively and so exclusively that alternative options appear as something to which lip service, rather than real investment, is usually paid. Yet, we must avoid the trap of an excessive ‘medicalization’ of the problem and we must first of all remind ourselves that schistosomiasis is a disease of poverty, so that its full control could be achieved, in principle, just by removing the socio-economic causes that lay at its basis [6]. We should not forget that the eradication of schistosomiasis from Japan was hardly dependent on drugs for its success [7]. The often-recommended ‘integrated approach’ to control schistosomiasis should comprise, among other measures, sanitation, water supply, ecological interventions and health education. In the transmission of schistosomiasis, snails are the intermediate hosts, but the real vector is man: it is a baffling truism that if people avoided urinating or defecating in or near water bodies, transmission would be automatically interrupted, at least in places where non-human hosts are absent. However, the rapid spread – even in the most deprived settings – of electronic communication tools seems to remain a largely underused opportunity to raise awareness of health problems. When the costs of interventions are taken into account, there is no doubt that PZQ chemotherapy is today a very good buy, especially when combined with the distribution of drugs against other parasites. PZQ is unquestionably providing enormous benefits to endemic populations, since, among other things, it helps break the vicious circle whereby poverty is a cause of disease and disease is a cause of poverty. However, a more farsighted approach should contemplate a substantial redressing of the balance from the present overwhelming preponderance of mass drug distribution in favor of other non-medical measures that may turn out to be more rewarding in the long run.

2. Vaccines The major shortcoming of chemotherapy is that it does not prevent re-infection, thus requiring repeated treatments of people living in endemic areas. Preventive vaccination would clearly overcome this problem and the quest for a schistosomiasis vaccine actually represents a sizeable portion in the records of schistosomiasis research. Toward the end of the 1970s, optimism about the feasibility of a vaccine was encouraged by the finding that mice exposed to irradiated cercariae exhibited over 80% resistance to a subsequent challenge with normal cercariae [8]. A number of

natural and recombinant antigens in various formulations were tested in an effort to identify the immunogen(s) active in irradiated cercariae, but none gave the expected high protection when tested in the mouse. WHO sponsored an independent trial to test six antigens proposed by various research groups, but the results were flatly negative, since none of them reached the minimum goal of 40% protection in the mouse [9]. This may be construed as a turning point, since in subsequent years vaccine research maintained a rather soft profile. Recent progress in the analysis of the schistosome genome, transcriptome and proteome, especially with regard to tegument proteins, has revived the hopes for a vaccine [10]. Undeniably though, the road to a safe, effective, long-lasting and cheap vaccine is still very long and frightfully crowded with uncertainties. 3. Molluscicides Until the 1970s, molluscicides were at the forefront of schistosomiasis control, to be later displaced by the newly available drugs for human use [11]. In spite of the adoption of a reasonably good chemical, niclosamide, the practice of mollusciciding has always faced serious problems. Local communities are understandably reluctant to accept that their water bodies turn yellowish while fish and other aquatic organisms undergo death and putrefaction [12]. The molluscicidal effects are short-lived and a few surviving snails are sufficient to subsequently re-populate treated sites. In addition, the cost of chemicals is far from negligible, especially for large water bodies. Today, the consensus seems to be that only under special circumstances focal mollusciciding may be recommended as an adjunct to chemotherapy and other measures. In spite of a substantial standstill in the practice of chemical snail control, a flourishing of reports has appeared over the years in the literature, regarding plant-derived molluscicides that could be potentially developed at the local level [13]. None of the proposed products, however, has been able, so far, to overcome the challenges of high efficacy and mass production. On a related topic, snail control has been attempted using predatory or competing organisms like fish, prawns or different snail species [14], but practical applications of this interesting approach are as yet unavailable. 4. Enter praziquantel The early events in the development of PZQ have been repeatedly reviewed [15–17]. A series of compounds synthesized at Merck, Germany, in a project designed to find new tranquillizers, were passed on to Bayer to be screened for anthelmintic activity. The astonishing fact is that the screening for antischistosomal activity of the initial compounds and of over 400 subsequently tested derivatives was carried out using mice infected with S. mansoni, complemented with in vitro observation of whole parasites [18]. Yet, the selected product, PZQ, is such a highly optimized compound that it is still unsurpassed for safety and antiparasitic efficacy among countless chemicals (analogs and otherwise) that have been tested up to this day. The reasons for PZQ success can be classified under four main headings: efficacy, safety, operational convenience, price. 4.1. Efficacy When measured by parasite egg excretion about four weeks after treatment with 40 mg/kg, the effects of PZQ can be very broadly summarized as 60–90% cure (no eggs in feces) and 80–95% average reduction in the number of excreted eggs in noncured patients. This can be regarded as a very good result, but it was

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pointed out [19] that 100% cure is seldom achieved and that these figures are probably overestimated due to the relative insensitivity of diagnostic methods. The standard dose of 40 mg/kg may be a subcurative one, but increasing the dose to 60 mg/kg does not seem to improve results [20]. Alternative explanations are thus necessary. An important fact in the mode of action of PZQ is that schistosomes are susceptible for the first few days after infection, but then susceptibility decreases to a minimum around day 28, to resume again gradually to a maximum after weeks 6-7 [21–23]. If an individual harbors immature parasites at the time of treatment – a situation most likely to occur in areas of intense transmission of infection – cure will not be achieved. This is probably an explanation for a few instances where unusually low cure was obtained [24]. To obviate the problem of low susceptibility of immature stages, it was proposed to administer a second dose of PZQ two weeks later [25], when immature forms have progressed to maturity, a procedure that actually resulted in higher cure rates [26]. As currently used, PZQ is a racemic mixture of two stereoisomers, only one of which is endowed with antischistosomal properties [18], while the other one contributes a portion of side effects [27], is responsible for the unpleasant taste of the medication [28] and represents 50% of the bulk of tablets that are often difficult to swallow for children. Current efforts to devise an economically viable production of PZQ as a single enantiomer [29] will hopefully result in a much improved drug. In addition to its schistosomicidal activity, PZQ exerts remarkable effects on a number of other trematodes (Opisthorchis, Paragonimus, Fasciolopsis, Heterophyes, Metagonimus spp.), with the notable exception of Fasciola spp. [30]. PZQ is also effective against most cestodes (Hymenolepis, Echinococcus, Diphyllobothrium, Taenia spp.), with the exception of some larval cestode infections, like hydatid disease and sparganosis [30]. It may be mentioned that, even before its introduction into human therapy, PZQ had been marketed as a dog cestocide under the name Droncit® . The activity of PZQ against these additional parasites clearly adds to its attractiveness in many areas where polyparasitism is often the rule. 4.2. Safety A massive amount of data has been collected over the years on the subject of PZQ safety, with regard to both immediate and delayed effects, and the overwhelming evidence points to the conclusion that PZQ may be considered the safest of all anthelmintic drugs. The same conclusion applies to different geographical settings [31], different parasite species [32], different patient ages [33] and conditions. Reversing previous practice, an informal WHO consultation concluded that pregnant and lactating women should also be treated, since the benefits of treatment clearly exceed hypothetical risks [34]. Short-term adverse reactions do occur in a significant number of cases, but they are usually mild and of short duration. The frequency and the severity of side effects is directly correlated with the pretreatment intensity of infection, suggesting that a proportion of the reactions are likely to be due to dying schistosomes and to the release of their products. Very rare instances of allergic reactions have been reported, but only in one case allergy could be directly attributed to PZQ on the basis of specific desensitization [35]. 4.3. Operational convenience Over 42 million people were treated with PZQ in 2012, an impressive figure, although it represents only 14.4% of the population estimated to be in need of treatment [36]. Such a large scale distribution occurred largely through the school system and was made possible by the fact that PZQ is given as a single oral dose, does not require direct medical supervision, does not produce

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serious side effects and can be easily dosed on the basis of children’s height [37]. On these premises, PZQ is generally administered by mass treatment without previous individual diagnosis. In high risk areas (50% prevalence of infection) all school-age children and all adults are targeted for treatment. The current strategy of preventive chemotherapy envisages – where co-endemicity exists – the simultaneous administration of medication against lymphatic filariasis, onchocerciasis and soiltransmitted helminthiasis, a practice that represents a formidable boost to the cost efficiency of chemotherapy campaigns. 4.4. Cost At the time of its introduction into human therapy, the cost of PZQ represented a major obstacle to its mass distribution, but already in 1983 the Korean company Shin Poong stepped into the market with a new manufacturing process and brought about a considerable price reduction. Nowadays the average cost of PZQ is around US$ 0.20 per treatment [38], while roughly the same amount is spent for drug distribution. Merck KgaA has pledged to make freely available up to 250 million tablets PZQ/year and other manufacturers and partner organizations will make additional contributions, but, as stated in a recent WHO document, ‘the gap in availability of praziquantel is huge and pledged amounts will not fill it in the near future’ [36]. 4.5. PZQ resistance The massive and exclusive use for many decades of a single drug has obviously raised legitimate fears that PZQ-resistant schistosomes may sooner or later appear. While the experience with other anti-infective agents justifies such fears on theoretical grounds, another theoretical consideration points to the opposite direction. As previously mentioned, only a minor proportion of people at risk actually receive treatment, thereby leaving ample ‘refugia’ [39] for sensitive parasites. Thus, it is sadly ironic that the very inability to provide complete drug coverage may prevent further disasters. Leaving aside theoretical considerations, one should ask whether any evidence for the development of PZQ resistance has appeared so far in the field or in the laboratory. Extremely low cure rates (18%) were reported in Senegal [24], but this occurred in a special focus of very intense transmission, suggesting that low cure may have been largely due to the presence of many immature parasites (see Section 4.1). Eggs obtained from treated and uncured Egyptian patients gave rise to schistosomes that showed decreased susceptibility when tested in the laboratory [40]. However, such insensitivity was only of moderate degree, was often unstable and investigations carried out ten years later in the same area failed to show any hint of PZQ resistance [41]. A number of travelers returning with schistosomiasis from endemic areas had to be repeatedly treated (sometimes unsuccessfully) to clear the infection. However, most of these were infections caused by S. haematobium (see [42] for a list) whose eggs are retained for a long time in tissues and diagnosis was rarely obtained on the basis of egg excretion. In any event, no highly resistant schistosome isolate was obtained from these patients. Also, it is possible that people coming from non-endemic areas may lack an immunological component that has been shown to contribute to PZQ activity in experimental animals [43]. Different geographical S. mansoni isolates were shown to differ in their sensitivity to PZQ [44], with somewhat lower susceptibility when coming from areas of previous PZQ usage, but differences were relatively modest and only detectable at low doses. A laboratory strain of S. mansoni was repeatedly subjected to sub-lethal PZQ doses in subsequent generations and drug-selected

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parasites were shown to exhibit a decreased susceptibility with respect to unselected schistosomes [45]. This partial resistance was confirmed in other laboratories, but, again, it was of rather limited magnitude. Genetic crosses between selected and unselected schistosomes indicated a co-dominant type of inheritance [46]. More recently, PZQ selection was carried out at the infected snail stage and the schistosomes thus obtained were reported to be less sensitive to PZQ at low and intermediate doses [47]. When all these pieces of information are taken together, it seems safe to conclude that no overt occurrence of PZQ resistance has appeared so far in the field and that reported sporadic cases of decreased drug sensitivity may often lend themselves to alternative explanations and are not of sufficient magnitude to undermine the public health value of PZQ. Likewise, laboratory data are based on relatively minor differences in PZQ sensitivity, at least when compared with the solid resistance to another antischistosomal drug, oxamniquine (see later). There is obviously no guarantee that serious PZQ resistance will never appear; the worry has solid rational justifications and the quest for alternative drugs is becoming more urgent every day. 4.6. Mechanism of action of PZQ It is remarkable that after so many years of use and so many million people treated, the mechanism of action of PZQ is still unsettled. However, the early effects exerted by the drug on the schistosome have been quite well described and can be summarized under three main headings: (i) calcium influx into whole parasites, (ii) muscle contraction and (iii) surface modifications [15]. It is tempting to link these three phenomena into a single thread, assuming that the key event is calcium influx, which in turn causes muscle contraction and tegument alterations. Evidence collected in recent years gives strong but not definitive support to this hypothesis [48]. It was initially observed that schistosomes possess two regulatory ␤ subunits of voltage-activated calcium channels, one of which can be defined ‘variant’ since it has an unusual structure and lacks two serine residues that constitute putative phosphorylation sites in the ‘conventional’ subunit. When the variant subunit was co-expressed in Xenopus oocytes together with a mammalian ␣1 subunit, the resulting channel exhibited a novel PZQ sensitivity, consisting in increased Ca2+ currents in the presence of the drug. A mutagenized variant subunit where the two candidate phosphorylation sites had been reconstituted, no longer exhibited this functional peculiarity. Conversely, a conventional mammalian ␤ subunit mutagenized to lose the two phosphorylation sites behaved functionally like the variant schistosome subunit. The idea that Ca2+ channels containing the variant ␤ subunit could be the target of PZQ action was reinforced by the finding that other organisms that are susceptible to PZQ (Taenia solium, Clonorchis sinensis) also possess the variant ␤ subunit. An apparently unrelated observation was made in the planarian Dugesia japonica, which is able to regenerate both its head and its tail when amputated at the two ends. If these planarians were exposed to PZQ soon after a double truncation, the resulting regenerated worms invariably presented two heads instead of a head and a tail [49]. Suppression of planarian calcium channel ␤ subunits by RNAi inhibited the double head phenomenon, although – contrary to expectation – inhibition was more pronounced when the conventional subunit, rather than the variant subunit, was suppressed. Thus, in spite of some conflicting details, even in this system the biological activity exerted by PZQ appears to be broadly dependent on the activity of calcium channels. The analogy between the schistosome and planarian systems has been recently extended to show that compounds inducing regenerative bipolarity are often endowed with antischistosomal properties and vice versa, implying

possible new research avenues to uncover antischistosomal drugs [50]. The schistosomicidal activity of PZQ can be partially inhibited by some classical calcium channel inhibitors (nicardipine, nifedipine) and is completely abolished if schistosomes are pre-incubated with the actin depolymerizing agent cytochalasin D [51]. This was initially interpreted as an effect of cytochalasin D on calcium channels (as documented in other mammalian systems), but it was later shown that PZQ-mediated calcium influx into the schistosomes is not at all inhibited by cytochalasin D, rather it is largely increased [52]. This presents us with the puzzling situation in which schistosomes inundated with a large amount of calcium fail to exhibit the expected sequence of events leading to tegument disruption and death. A completely analogous coexistence of high calcium levels and of undisturbed survival is presented by immature stages of S. mansoni exposed to PZQ, to which they are largely insensitive. These phenomena seem to contradict the basic assumption that calcium is the key agent of PZQ schistosomicidal effects, but it must be admitted that our knowledge of the detailed molecular events connected with PZQ activity are still rather crude [52]. A number of alternative hypotheses on PZQ mechanism of action have been put forward and are detailed in previous reviews [15,53]. 4.7. Summary considerations on PZQ PZQ is not a perfect drug. Its major fault is the lack of activity against immature schistosomes, a potential source of unsatisfactory results upon mass administration. Its racemic composition contributes undue amounts of side effects and complicates practical administration. Its still unclear mechanism of action prevents the rational design of improved analogs. Finally, even if PZQ were an intrinsically perfect drug, its being the only medication available against schistosomiasis would urge the development of alternative drugs. The fact that no clinically relevant resistance has appeared over thirty years after its introduction is another fantastic testimony to the qualities of PZQ, but cannot be taken as a guarantee for the future. The combined high standards of safety and efficacy make PZQ a drug that is very hard to beat or even to match, but the challenge cannot be shirked. 5. Other drugs The number of compounds that have been tested as possible antischistosomal agents is so large that it would be difficult to acknowledge them all. What follows is an incomplete mention of those compounds that, as of now, appear to hold some promise for the development of new antischistosomal drugs. 5.1. PZQ derivatives A relatively small number of PZQ derivatives have been synthesized and tested after the introduction of the parent drug into human use. No compound promised better performance than PZQ and scanty information could be derived from structure–activity relationships. Modifications of the aromatic ring generally led to decreased activity [54]; moderate activity against juvenile worms was found in some compounds, but was not accompanied by satisfactory performance against adults [55]; substitutions in the cyclohexyl group gave compounds with decreased activity [56]. 5.2. Oxamniquine Certainly not a new drug, oxamniquine (OXA) was used long before the introduction of PZQ, to treat many millions of people infected with S. mansoni. The main limitation of OXA is that it is not

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Fig. 1. The circular sequence of images connected by black arrows illustrates the various stages of S. mansoni life cycle. Yellow boxes indicate different approaches that can be exploited to interrupt the life cycle (red arrows). Notice that praziquantel and oxamniquine are not active on immature worms, whereas artemisinins and antimalarials are mainly active on this very stage.

active against S. haematobium or S. japonicum, a fact that discouraged its use outside of South America, where only S. mansoni exists. The restricted market of OXA prevented its competitive production and the expected price reduction, so that today PZQ is cheaper than OXA and has replaced it even in countries, like Brazil, where OXA has been for many years the successful cornerstone of control programs. With respect to both safety and efficacy against S. mansoni, OXA has proved to be at least as good as PZQ, sharing its advantages of single oral administration and mild side effects [15]. Sporadic instances of OXA resistance observed in Brazil and the duplication of the phenomenon in the laboratory permitted the isolation of S. mansoni strains that were highly refractory to the drug, surviving doses ∼500-fold higher than those that are lethal to sensitive parasites. Genetic crosses between sensitive and resistant schistosomes led to the conclusion that OXA resistance is a recessive trait controlled by a single autosomal gene [57]. This suggested the existence of a schistosome ‘factor’ that is essential to convert the prodrug OXA into the active compound. A series of further biochemical data (summarized in [58]) narrowed down the hypothesis and predicted that a parasite sulfotransferase is the activating enzyme and that a loss of its function is at the basis of OXA resistance [59]. This prediction was recently confirmed using a linkage mapping approach that unambiguously identified the S. mansoni sulfotransferase gene and permitted the crystallographic analysis of the enzyme and of its interaction with the drug [60]. This represents the first complete elucidation of an anthelmintic drug’s mechanism of action, and – most importantly – opens the way to a structure-based redesign of OXA to extend its activity to the S. haematobium sulfotransferase analog. Thus, it is now a realistic hope that a new broad-spectrum OXA may represent the long sought-after partner/substitute of PZQ.

5.3. Antimalarial drugs Derivatives of artemisinin are known for their antimalarial activity, but have also been found to possess antischistosomal properties. In general, these types of compounds have the notable

characteristic of being more active against the immature schistosome stages than against the adults – just the opposite of PZQ – a feature suggesting combined treatments as their ideal utilization (Fig. 1). Results from clinical trials show that artesunate alone gives lower cure rates than PZQ, while a combination of an artemisinin derivatives plus praziquantel is more effective than PZQ alone [61]. Taking advantage of the activity of artemisinins on early stages of infection, a prophylactic approach consisting of the administration of repeated doses of these drugs proved to confer significant protection when compared to placebo [61]. A limitation to the use of artemisinins against schistosomiasis consists in the risk that this may favor the development of drug resistant plasmodia in areas of coendemicity. Artemisinins contain an endoperoxide bridge that is implicated in their mechanism of action. Synthetic endoperoxide-containing compounds are currently the object of active research and some promising leads have been identified that are effective against both adult and immature schistosomes [62]. Another antimalarial drug that was found to possess antischistosomal activity is mefloquine [63]. As with artemisinins, activity against immature schistosomes is higher than against adults. Mefloquine derivatives are currently under investigation.

5.4. Furoxan While the antioxidant defenses of vertebrates are largely dependent on two enzymes, glutathione reductase and thioredoxin reductase, schistosomes rely on a single multifunctional selenocysteine-containing enzyme, thioredoxin–glutathione reductase (TGR) [64,65]. This enzyme is essential for parasite survival and has been the target of extensive high throughput screens leading to the identification of oxadiazole 2-oxides as a class of potential antischistosomal agents [66]. One of these compounds, furoxan, showed in vitro activity against adult and juvenile worms at ␮M concentrations, was highly effective in vivo when administered once daily for 5 days by intraperitoneal injections and had a toxicity slightly higher than PZQ for mammalian cells.

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6. Bioinformatics and high throughput screenings Recent advances in genome sequencing and the availability of functional databases have become essential prerequisites and complements for any large scale investigation of parasite targets and potential drugs. The creation of a ‘TDR targets database’ well exemplifies this trend [67]. Along similar lines, the differential analysis of schistosome transcripts before and after exposure to PZQ has been used as a tool to identify drug targets [68]. The successful exploitation of high throughput screening of compound libraries using a defined molecular target (typically an enzyme) has been exemplified above with regard to furoxan [64]. Such defined targets, however, are not commonly available and resort is made to whole organisms in vitro. In this case, larval stages are preferred to adult parasites because they are more easily available in large numbers, but one has to take into account the different drug susceptibility of different life cycle stages. Screening can be based on various methods of parasite labeling or even on the automatic detection of morphological changes [69]. 7. Concluding remarks It is possible that PZQ may remain the antischistosomal drug of choice for many additional years. However, since the looming development of resistant parasites would represent an enormous disaster for millions of people, it is imperative that alternative intervention tools be actively researched and promptly developed. References [1] Kloos H, David R. The Paleoepidemiology of Schistosomiasis in Ancient Egypt. Human Ecol Rev 2002;9:14–25. [2] Chitsulo L, Engels D, Montresor A, Savioli L. The global status of schistosomiasis and its control. Acta Trop 2000;77:41–51. [3] Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 2006;6:411–25. [4] van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125–39. [5] King CH, Dickman K, Tisch DJ. Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 2005;365:1561–9. [6] Evans AC, Stephenson LS. Not by drugs alone: the fight against parasitic helminths. World Health Forum 1995;16:258–61. [7] Tanaka H, Tsuji M. From discovery to eradication of schistosomiasis in Japan: 1847–1996. Int J Parasitol 1997;27:1465–80. [8] Minard P, Dean DA, Jacobson RH, Vannier WE, Murrell KD. Immunization of mice with cobalt-60 irradiated Schistosoma mansoni cercariae. Am J Trop Med Hyg 1978;27:76–86. [9] Wilson RA, Coulson PS. Schistosome vaccines: a critical appraisal. Mem Inst Oswaldo Cruz 2006;101(Suppl 1):13–20. [10] Bethony JM, Cole RN, Guo X, Kamhawi S, Lightowlers MW, Loukas A, et al. Vaccines to combat the neglected tropical diseases. Immunol Rev 2011;239:237–70. [11] Sturrock RF. Schistosomiasis epidemiology and control: how did we get here and where should we go? Mem Inst Oswaldo Cruz 2001;96(Suppl.):17–27. [12] Takougang I, Meli J, Wabo Poné J. Angwafo F 3rd. Community acceptability of the use of low-dose niclosamide (Bayluscide), as a molluscicide in the control of human schistosomiasis in Sahelian Cameroon. Ann Trop Med Parasitol 2007;101:479–86. [13] Hostettmann K, Lea PJ. Biologically active natural products. Oxford, UK: Oxford Science Publication; 1988. [14] Sokolow SH, Lafferty KD, Kuris AM. Regulation of laboratory populations of snails (Biomphalaria and Bulinus spp.) by river prawns, Macrobrachium spp. (Decapoda Palaemonidae): implications for control of schistosomiasis. Acta Trop 2014;132:64–74. [15] Cioli D, Pica-Mattoccia L, Archer S. Antischistosomal drugs: past, present . . . and future? Pharmacol Ther 1995;68:35–85. [16] Cioli D, Pica-Mattoccia L. Praziquantel Parasitol Res 2003;90(Suppl. 1):S3–9. [17] Pica-Mattoccia L, Cioli D. Praziquantel: too good to be replaced? In: Caffrey CR, editor. Parasitic helminths targets, screens, drugs, and vaccines. Weinheim: Wiley-Blackwell; 2012. p. 309–21. [18] Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel Med Res Rev 1983;3:147–200.

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