Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers.

Abstract

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...

Schistosomes—proteomics studies for potential novel vaccines and drug targets

“…Further in vitro experiments confirmed the development of parasite resistance to Praziquantel compared with susceptible isolates [8][9][10][11]. It is still controversial whether the low cure rates observed can be correlated with the emergence of Praziquantel-resistant parasites, because the interpretation of data is complicated by other factors, such as reinfection of patients in the field, varying sensitivity of diagnostics techniques utilized and the presence of non-susceptible immature worms in the patients [12,13].…”

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

“…Praziquantel is the sole drug available for controlling schistosomiasis, with schistosome-resistant parasites now becoming an increasingly worrying problem. 72,73 Ivermectin is a potent agonist of glutamate-gated chloride channels and as glutamate signaling has been recorded in schistosomes, 74,75 there may be an ivermectin target in the tegument. Workers in Egypt evaluating the effect of ivermectin on mice infected with Schistosoma mansoni, concluded that ivermectin has promising anti-schistosomal effects.…”

Un nouvel espoir dans le traitement de la schistosomiase

“…Toutefois, le traitement par le Praziquantel est très peu actif sur les formes jeunes du parasite dans les infections récentes. Il doit donc être renouvelé régulièrement et l'utilisation massive du Praziquantel en zones d'endémie laisse présager l'apparition de souches parasitaires résistantes, certains isolats moins sensibles ayant déjà été identifiés [3]. Pour cela, l'OMS (Organisation Mondiale de la Santé) a défini comme une priorité stratégique la recherche de nouveaux médicaments contre les schistosomes.…”