Use of PZQ will increase in the foreseeable future, whether given alone or coadministered with other anthelminthics in integrated control programmes. PZQ resistance remains a threat and its prevention requires adequate monitoring of current mass drug administration programmes and development of new schistosomicides.

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Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

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S U M M A R YTreatment with praziquantel (PZQ) has become virtually the sole basis of schistosomiasis control in sub-Saharan Africa and elsewhere, and the drug is reviewed here in the context of the increasing rate that it is being used for this purpose. Attention is drawn to our relative lack of knowledge about the mechanisms of action of PZQ at the molecular level, the need for more work to be done on schistosome isolates that have been collected recently from endemic areas rather than those maintained in laboratory conditions for long periods, and our reliance for experimental work mainly on Schistosoma mansoni, little work having been done on S. haematobium. There is no evidence that resistance to PZQ has been induced in African schistosomes as a result of its large-scale use on that continent to date, but there is also no assurance that PZQ and/ or schistosomes are in any way unique and that resistant organisms will not be selected as a result of widespread drug usage. The failure of PZQ to produce complete cures in populations given a routine treatment should therefore solicit considerable concern. With few alternatives to PZQ currently available and/or on the horizon, methods to monitor drug-susceptibility in African schistosomes need to be devised and used to help ensure that this drug remains effective for as long a time as possible.

Evidence for resistance to praziquantel (PZQ) in Schistosoma mansoni has been sought in parasites taken from treated, but uncured human patients, and in a laboratory isolate of S. mansoni subjected to successive passages under drug pressure. Patients from villages in Egypt and Senegal have yielded isolates that can tolerate higher dosages of PZQ than other ostensible control isolates when passaged and subjected to drug treatment in mice. In vitro tests on these and the laboratory-selected isolate support the conclusion that a degree of resistance to PZQ can occur in S. mansoni, but the levels of drug resistance found so far are low. Preliminary studies have begun on these isolates to identify genetic, physiological and morphological characteristics associated with PZQ resistance and some of these may find use as markers for monitoring whether or not resistance is developing in endemic areas where the drug is used. More intensive application of PZQ can be expected in future, particularly in other parts of Africa, and vigilance will be needed to ensure that it continues to be useful as a drug for treatment of schistosomiasis. Further work is needed to elucidate the mode of action of PZQ and there is already a need for alternative drugs to treat PZQ-resistant schistosomiasis, such as already exists in northern Senegal.