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In the current era of intensified and integrated control against schistosomiasis and other neglected tropical diseases, there is a need to carefully rethink and take into consideration disease-specific issues pertaining to the diagnosis, prevention, control and local elimination. Here, we present a comprehensive overview about schistosomiasis including recent trends in the number of people treated with praziquantel and the latest developments in diagnosis and control. Particular emphasis is placed on children. Identified research needs are offered for consideration; namely, expanding our knowledge about schistosomiasis in preschool-aged children, assessing and quantifying the impact of schistosomiasis on infectious and noncommunicable diseases, developing new antischistosomal drugs and child-friendly formulations, designing and implementing setting-specific control packages and developing highly sensitive, but simple diagnostic tools that are able to detect very light infections in young children and in people living in areas targeted for schistosomiasis elimination.

The design, synthesis and biological evaluation of eighteen ferrocenyl derivatives (4A-12A and 4B-12B) of the most-well known drug against schistosomiasis, namely praziquantel (PZQ), are reported.These compounds which have been all isolated as racemates were unambiguously characterized by 1 H and 13 C NMR spectroscopy, mass spectrometry and elemental analysis as well as by X-ray crystallography for 4A, 5A and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic towards a cervical cancer cell line (HeLa) and, importantly, significantly less active towards a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the eighteen ferrocenyl PZQ derivatives was tested against Schistosoma mansoni and values in the micromolar range (26-68 µM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37°C in human plasma. 3Introduction.

BackgroundThe development of novel antischistosomal drugs is crucial, as currently no vaccine and only a single drug is available for the treatment of schistosomiasis. Fast and accurate in vitro assays are urgently needed to identify new drug candidates and research efforts should include Schistosoma haematobium. The aim of the present study was to develop a S. haematobium drug sensitivity assay based on newly transformed schistosomula (NTS).MethodsWe first undertook comparative studies on the cercarial emergence rhythms of the intermediate host snails Biomphalaria glabrata (S. mansoni) and Bulinus truncatus (S. haematobium). Two transformation methods as well as three purification methods were studied on S. haematobium cercariae in order to produce a large number of viable and clean NTS. Known antischistosomal drugs were tested in the established NTS assay in vitro. Drug effects were evaluated either microscopically or fluorometrically, using a resazurin based viability marker. Microscopically obtained IC50 values were compared with results obtained for S. mansoni.ResultsA circadian rhythm existed in both snail species. Infected B. truncatus snails shed less cercariae than B. glabrata during the testing period. The highest transformation rate (69%) of S. haematobium cercariae into NTS was obtained with the vortex transformation (mechanical input) and the highest purification factor was observed using Percoll®. The fluorimetric readout based on resazurin was very precise in detecting dead or/and severely damaged schistosomula.ConclusionsWith the use of viability markers such as resazurin, drug screening assays using S. haematobium NTS can be efficiently performed. However, drugs acting on the morphology and motility of S. haematobium NTS, such as metrifonate are missed. Drug sensitivity assays with NTS of both species, S. haematobium and S. mansoni, showed very similar results using known antischistosomal drugs. The S. mansoni NTS assay might be more suitable as primary screen in drug discovery efforts, which ultimately aim for a broad-spectrum antischistosomal drug as a larger number of S. mansoni NTS can be generated.

We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound. S chistosomiasis, caused by blood flukes of the genus Schistosoma, is an important cause of morbidity and mortality, mainly among the rural poor in sub-Saharan Africa (5, 16). The need for new antischistosomal drugs is quite evident, given that praziquantel is the only drug available and is in widespread use in population-based morbidity control programs (16).Various classes of synthetic peroxides, including trioxaquines (1,2,4-trioxanes) (1, 12), the tetraoxaspirononadecane N-89 (15), and ozonides (1,2,4-trioxolanes) (19), have been studied for their antischistosomal properties. Our previous data demonstrate that, like the artemisinins, ozonides possess promising antischistosomal properties (10, 19). We investigated three representative ozonides, namely, carboxylic acid OZ78, amine OZ209, and phenol OZ288 (Fig. 1). Of these, 8=-aryl ozonide OZ288 had the highest antischistosomal activity; this ozonide reduced the total worm burden by 95% (200 mg/kg body weight) in mice harboring juvenile Schistosoma mansoni and by 52% (400 mg/kg) in mice harboring adult worms (19). Although 8=-alkyl ozonides OZ78 and OZ209 had activities greater than 80% against juvenile worms, lower activities (0 and 17%, respectively) were observed for these two ozonides against adult worms. We suggest that the increased iron(II) stabilities of 8=-aryl ozonides compared to those of 8=-alkyl ozonides (2) might contribute to the superior antischistosomal efficacy of OZ288.The aim of the present study was to evaluate in a first step the in vivo antischistosomal activities of nine structurally diverse OZ288 analogs (Fig. 2), including antimalarial drug candidate OZ439, currently in phase II clinical testing (2). Since schistosomiasis and malaria are coendemic in many parts of the world, it is important to assess the potential auxiliary effects of antimalarial drug candidates such as OZ439 on Schistosoma species.Our animal studies were carried out following national and cantonal regulations on animal welfare (permission no. 2070). All compounds were synthesized as described in previous publications and patents (3,4,17,18). Compounds were freshly prepared in homogenous aqueous suspensions in 7% Tween 80 and 3% ethanol.Female NMRI mice (n ϭ 147; age, 4 weeks; weight, ϳ20 g) were purchased from Charles River (Sulzfeld, Germany) and Harlan Laboratories (Blackthorn, United Kingdom). Mice were maintained in groups of 10 in Makrolon cages under environmentally controlled conditions (temperature, ϳ25°C; humidity, ϳ50%; 12-h light and 12-h dark cycle) with free access to water and food. Mi...

H uman schistosomiasis is a neglected tropical disease whose burden is mainly concentrated in sub-Saharan Africa and affects approximately 207 million people (30). The three main schistosome species parasitizing humans are Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum. Today, treatment with praziquantel is the core component of schistosomiasis control programs (32,34,35). There is no question that heavy reliance on a single drug bears a risk of drug resistance development. Indeed, in different regions of endemicity, lower cure rates have already been observed (9). An additional disadvantage of praziquantel is its stage-dependent susceptibility, showing only poor efficacy against immature schistosome stages (23). Therefore, drug discovery in the field of schistosomiasis remains an important task. Antischistosomal properties of the antimalarial drug mefloquine were first mentioned in 2008, when it was shown that a dosage of 150 mg/kg of body weight significantly reduced the egg burden in S. mansoni-infected mice (33). Further investigations revealed that mefloquine possesses good in vivo efficacy, with a single oral dosage of 200 mg/kg resulting in a total worm burden reduction of 72.3% in S. mansoni-infected mice. Another interesting characteristic of mefloquine is its efficacy against the juvenile immature stage (13). Finally, a randomized clinical trial that investigated the effect of mefloquine and mefloquine-artesunate in S. haematobium-infected patients was recently performed. It was shown that a combination therapy of mefloquine-artesunate resulted in moderate cure and high egg reduction rates (15).Based on these promising findings, we were motivated to test mefloquine-related compounds belonging to the three major groups of arylmethanols well described in antimalarial research, namely, 4-quinolinemethanols, 9-phenanthrenmethanols, and 4-pyridinemethanols (4), in order to elucidate their potential as antischistosomal lead candidates. In addition, a study on mefloquine-related compounds might provide us with a deeper understanding of structural features needed for antischistosomal activity of arylmethanols. The selected nine arylmethanols were first tested against S. mansoni schistosomula and adults in vitro. Promising compounds were followed up in vivo. Candidates characterized by high in vivo activity against S. mansoni were tested against S. haematobium. In addition, promising candidates were incubated in the presence of hemoglobin, hemin, or red blood cells to compare drug activities in relation to the postulated mechanistic heme dependency of arylmethanols (6). Finally, isothermal microcalorimetry (IMC) was used to investigate the antischistosomal properties of lead candidates in greater detail and to compare their levels of activity with mefloquine.

The antischistosomal effect of two [(η(6)-praziquantel)Cr(CO)(3)] derivatives was investigated. The compounds (see figure: Cr purple, N blue, O red) were prepared in a one-step procedure from commercially available praziquantel. Both derivatives show a high in vitro activity against Schistosoma mansoni, a parasitic trematode, and only a minor cytotoxic effect on selected mammalian cell lines.

We successfully applied a newly developed classification model to prioritise medication handling errors for prevention strategies.