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Botros SS, Hammam O, Mahmoud M, Bergquist R. Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessment. APMIS 2010; 118: 692–702. Based on the fact that artemether (ART) affects immature schistosomes and that the effect of praziquantel (PZQ) mainly targets mature schistosomes, this work investigates the possible enhanced efficacy of PZQ in combination with ART in mice harboring a PZQ non-susceptible Schistosoma mansoni isolate. Associated schistosomal, inflammatory, hepatic histopathological changes have been investigated by examining the tissue markers expressing apoptosis using FAS (CD95), anti-apoptosis (Bcl2) and angiogenesis [vascular endothelial growth factor (VEGF)]. A batch of Swiss albino mice infected with a PZQ non-susceptible (EE10) S. mansoni isolate was divided into 12 groups. Animals of the first group were left without treatment as infected controls, while groups 2–6 received PZQ in increasing doses. The animals of group 7 received ART in double doses. Those comprising groups 8–12 received combined therapy of PZQ and ART in the same doses and at the same timings postinfection (PI) as those belonging to groups 2–6. Parasitological parameters, liver function, and histopathological and immunohistochemical studies of FAS, Bcl2 and VEGF antibodies were assessed. Combined administration of ART and PZQ reduced the ED50 (the dose at which the worm burden was decreased by 50%) of PZQ. Typical granulomas were not seen in animals treated with ART alone and combined with PZQ, with least expression of FAS and VEGF and increased expression of Bcl2. The minimal histopathological changes recorded in mice treated with both ART and PZQ could be related to a synergistic/additive effect of ART, markedly reducing the intensity of infection. Improved liver function tests support the less severe histopathological changes under the influence of this treatment protocol. This study encourages human trials especially in areas where malaria is not endemic, and differing combination doses should be investigated in view of the antagonistic effect noticed with some dose regimens.

This work investigated the possible use of AdDP as adjuvant therapy to praziquantel (PZQ) in mice infected with PZQ-insusceptible Schistosoma mansoni isolate in a trial to increase the susceptibility of this isolate to the drug. Two batches of C57 BL/6 mice were infected with PZQ-susceptible and -insusceptible S. mansoni isolates, and each batch was divided into five groups. Seven weeks postinfection, the experimental group received AdDP (5 mg/kg) in addition to PZQ in reduced dose (3x100 mg/kg). Three of the remaining four groups were treated controls; they received AdDP, PZQ in reduced dose and in full dose (2x500 mg/kg), and the fourth group was infected untreated. In mice infected with PZQ-susceptible or -insusceptible S. mansoni isolate, praziquantel alone, and in addition to AdDP, reduced worm and egg loads and increased percentage dead eggs. Also, they improved the histopathological changes (reduction in granuloma diameter, percentage fibrotic area with increased percentage degenerated eggs). Inducible nitric oxide synthase (iNOS), nitric oxide (NO) in culture of peritoneal macrophages, and number of CD68-positive cells were decreased with improved alanine amino transaminase. In mice receiving combined therapy AdDP+PZQ, the antischistosomal efficacy and the reductions in the inflammatory granulomatous reactions, NO in cultured peritoneal macrophages, percentage fibrotic areas recorded, were comparable to that in mice receiving full dose of PZQ, with significantly higher reduction in CD68 cells denoting enhanced antischistosomal efficacy and healing of the inflammatory reactions in the liver.

After placement in mice of PZQ-sensitive and -insensitive S. mansoni isolates obtained from villagers responding and not responding to PZQ, parasitological criteria reflecting their biological development and also the host anti-immature worm immunoglobulin isotypes were examined 8 and 10 weeks post infection. Hepatic granuloma diameter, hepatic histopathological changes and immunolocalization of IgG and IgM on the surface of PZQ-sensitive and -resistant worms were also examined 10 weeks post infection. Data showed that parasitological criteria were not significantly different between mice infected with the PZQ-sensitive and -insensitive S. mansoni isolates. As regards serum immunoglobulins, in mice infected with the PZQ-insensitive S. mansoni isolate, IgG and IgG1 were significantly (p0.05) lower 8 and 10 weeks post infection, respectively (1.41+/-0.07 and 1.08+/-0.10 and 1.35+/-0.06 and 1.09+/-0.07) than in mice infected with the PZQ-sensitive S. mansoni isolate (1.73+/-0.15 and 1.38+/-0.10 and 1.73+/-0.17 and 1.54+0.21) after the same observation periods. IgM level was nearly the same while IgE was lower than that recorded in mice infected with the PZQ-sensitive S. mansoni isolate. IgG immunofluorescence was also lower (60%+/-6.78) on the surface of resistant worms than that of sensitive worms (66.6%+/-5.27); meanwhile, hepatic granuloma diameter was significantly larger (296.5+/-3.0 vs 283.6+/-4.0) in mice infected with the PZQ-insensitive S. mansoni isolate with higher percentage of intact eggs. Differences in the immunogenic make up of PZQ-sensitive and -insensitive S. mansoni isolates qualitatively and/or quantitatively favoring a certain Th cell subpopulation response could be the underlying reason for such differences recorded in the host immunoglobulin isotype response and also the egg-induced hepatic histopathological changes.