Abstract. Recent evidence suggest that resistance to praziquantel (PZQ) may be developing. This would not be surprising in countries like Egypt where the drug has been used aggressively for more that 10 years. The classic phenotype of drug resistance is a significant increase in the 50% effective dose value of isolates retrieved from patients not responding to the drug. In a previous publication, we reported that such phenotypes have been isolated from humans infected with Schistosoma mansoni. Since the action of PZQ may be dependent upon the drug and host factors, most notably the immune system, we analyzed the quantitative effects of PZQ on single worms that differed in their response to PZQ when maintained in mice. Our hypothesis was that the in vitro action of the drug would correlate with it in vivo action. We confirmed this hypothesis and conclude that the in vitro action of the drug is related to its in vivo action. Knowing this relationship will assist in our ability to detect or survey for the PZQ resistant phenotype in human populations.Praziquantel (PZQ) is used for the treatment of infections caused by Schistosoma spp. 1 In a number of regions, including much of Egypt, PZQ has been copiously used, and the impact of the drug on schistosome infections has been significant. 2,3 In the laboratory, exposure of schistosomes to subcurative doses of PZQ over generations resulted in drugresistant schistosomes, 4 demonstrating the possibility of resistance arising in the field. Indeed, reports of resistance in the field have recently appeared. 5 However, the reality of these reports is difficult to establish because it is often difficult to distinguish between host factors and parasite factors when patients are not cured of schistosomiasis with normally effective doses. First, since the host immune system plays an active role in the process of killing PZQ-damaged worms, 6 normal parasites might survive treatment in immunocompromised hosts. In vivo studies can also be confounded by the fact that PZQ is less effective in killing immature parasites, 7 such that a wide range of host factors inhibiting development of the parasites can cause an apparent decrease in drug efficacy. Variability of host PZQ metabolism can also cause variability of efficacy. 8 In an effort to minimize the variability of these host factors, parasites isolated from patients not cured by antischistosomal drugs have been used to establish experimental infections in less-variable laboratory animal hosts. 9 If infections produced by these isolates are not cured by normal doses of PZQ, it suggests that the decreased responsiveness of the isolates is due to worm factors rather than host factors. However, this type of assessment is a rather toilsome process.Despite the dependence of PZQ on the host immune system for killing the parasites in vivo, PZQ has dramatic, measurable effects on schistosomes in vitro. The three hallmark effects are contraction of the worm musculature, 10 an influx of calcium into the worm, 11 and disruption of the tegument...

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The aggressive use of praziquantel to combat schistosomiasis in Egpyt raises concern about the possible emergence of resistance. Eggs from Egyptian patients with praziquantel-resistant infections (not cured by 3 doses of praziquantel) have been used to establish infection-specific schistosome isolates in mice. The response of these worms to the drug was observed in vitro, in order to determine if the isolates obtained from these resistant infections were, in fact, less responsive to praziquantel. One of the hallmark effects of praziquantel on schistosomes in vitro is a disruption of the worm's outer surface, the tegument. Here, praziquantel-induced tegumental damage is observed in 3 distinct isolates, 2 derived from resistant infections and 1 from an infection cured by a single dose. The isolates from the resistant infections were less susceptible to praziquantel-induced tegumental damage in vitro, suggesting that the worms are in some way less responsive to the drug.

Schistosomiasis, a high volume neglected tropical disease affecting more than 200 million people worldwide, can only be effectively treated by the tetrahydroisoquinoline drug praziquantel (PZQ). Herein, we describe an efficient approach to access PZQ derivatives by the Ugi 4-component reaction followed by the Pictet-Spengler reaction in a two-step, one-pot procedure. 30 Novel PZQ derivatives are described based on the Ugi 4-component reaction and an X-ray structure of a novel derivative revealing different conformation compared with PZQ is discussed. Several analogues comparable in activity to the drug PZQ have been identified based on an in vitro Schistosoma mansoni worm viability assay.

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A series of benzothiazol-2-yl-dithiocarbamates 3a-d along with their copper complexes 4a-c were synthesized via the reaction of suitable alkyl, aralkyl or heteroaryl halides with the sodium salt of benzothiazol-2-yl-dithiocarbamic acid, followed by complexation with copper sulphate. N-(4-Acetyl-5-aryl-4,5-dihydro-1,3,4-thiadiazol-2-yl)-N-benzothiazol-2-yl-acetamides 7a-c were synthesized by cyclization of the appropriate thiosemicarbazones 6a-c in acetic anhydride. Selected compounds were screened for in vitro schistosomicidal activity against Schistosoma mansoni at three different dosage levels (10, 50 and 100 μg/ mL). Three of these products, 4a-c, showed schistosomicidal activity similar to praziquantel, with 100% worm mortality at 10 μg/mL. These compounds would constitute a new class of potent schistosomicidal agents.

The activity of the acyclic nucleotide analogue 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA] against Schistosoma mansoni was investigated in mice. The compound was injected intraperitoneally, usually on two or five consecutive days, at 10 to 20 mg/kg of body weight/day. The treatment started before, at the time of, and after the onset of egg laying (oviposition) by S. mansoni. The animals were killed from 7 to 40 days after the cessation of treatment. Significant reductions in the total numbers of female and coupled worms were found. Female fecundity and both hepatic and intestinal egg loads were suppressed. These effects were more pronounced with dosing regimens launched before the time of oviposition. The complete disappearance of immature eggs and a significant reduction to the complete absence of mature eggs, with 99 to 100% of the eggs being dead, were produced. No hepatic egg-induced granulomas were present in mice treated at the time of oviposition, and the granulomas were smaller in mice treated before S. mansoni oviposition. These preliminary findings extend the knowledge of the antiparasitic properties of (S)-HPMPA.

In a multicenter investigation of the potential antischistosomal activity of myrrh, a resin obtained from an African plant, different derivatives of the resin, including the commercial preparation Mirazid, were tested at different doses in mice and hamsters infected with Schistosoma mansoni. In mice infected with the Egyptian (CD) strain of S. mansoni, four of six groups treated with Mirazid did not show significant worm reduction, while the remaining groups showed significant but trivial reductions. In mice infected with the Puerto Rican (Mill Hill) strain of S. mansoni, a Mirazid solution was toxic for mice at high doses and produced modest or no worm reduction at lower doses. In hamsters and mice infected with Puerto Rican (NMRI) and Brazilian (LE) strains of S. mansoni and treated with the crude extract of myrrh in doses ranging from 180 to 10,000 mg/kg, no signs of antibilharzial activity were observed. Total tissue egg load and egg developmental stages were not affected by any of the treatment regimens. These results were in contrast to those obtained in praziquantel-treated animals in which 94% worm reduction and 100% egg reduction was observed. Based on the findings of this work, we cannot recommend the use of Mirazid in human cases of schistosomiasis.