Sabra Abdel Nasser A, Botros Sanaa S
Department of Pharmacology, Theodor Bilharz Research Institute, Warrak el-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt.
J Parasitol. 2008 Apr;94(2):537-41. doi: 10.1645/GE-1297.1.
The stability of praziquantel (PZQ)-insusceptible S. mansoni isolates and the possible selection of PZQ-insusceptible parasites upon applying therapeutic pressure were examined over several life cycle passages (snails to mice). To test isolate stability, 3 PZQ-susceptible and 7 PZQ-insusceptible isolates were used to establish infection in mice, and they were passaged each for 2-5 life cycles. After each passage, 6 groups of mice were used to assess the PZQ dose at which the worm burden was decreased by 50% (ED50). Five of them were treated with doses of PZQ (12.5, 25, 50, 100, and 200 mg/kg for 5 days) 7 wk after infection; the last group represented infected, but untreated, controls. Possible selection of PZQ-insusceptible parasites under therapeutic pressure was examined by subjecting 1 PZQ-susceptible and 1 PZQ-insusceptible S. mansoni isolate to therapeutic pressure by PZQ for 8 passages. After the final passage, PZQ ED50 was estimated. All PZQ-susceptible S. mansoni isolates showed stable susceptibility to PZQ (mean PZQ ED50 = 85 mg/kg) over all passages. Two of the 7 PZQ-insusceptible S. mansoni isolates (847 and ER5) showed normal sensitivity to PZQ in 1-2 passages (although not the last passage, and without a declining ED50 profile), whereas the remaining passages kept a sustained insusceptibility to the drug (mean PZQ ED50 = 217 mg/kg). Worm maturity and sex were irrelevant to variability in drug ED50 within an individual isolate over different passages, revealing the heterogeneous nature of the parasite. Therapeutic pressure for limited life cycle passages did not result in a significant increase in drug ED50. The fact that reversion of some of the PZQ-insusceptible S. mansoni isolates to normal drug-sensitive state is not long lasting and that the therapeutic pressure by PZQ in the field is not comparable with that in the laboratory (unlimited), make monitoring the response of patients to the drug in the field an integral part of schistosomiasis control measures.
通过几个生命周期传代（从蜗牛到小鼠），研究了对吡喹酮（PZQ）不敏感的曼氏血吸虫分离株的稳定性，以及施加治疗压力后可能出现的对PZQ不敏感寄生虫的选择情况。为了测试分离株的稳定性，使用3个对PZQ敏感和7个对PZQ不敏感的分离株感染小鼠，并分别传代2 - 5个生命周期。每次传代后，用6组小鼠评估使虫负荷降低50%的PZQ剂量（ED50）。其中5组在感染后7周用不同剂量的PZQ（12.5、25、50、100和200 mg/kg，连用5天）进行治疗；最后一组为感染但未治疗的对照组。通过对1个对PZQ敏感和1个对PZQ不敏感的曼氏血吸虫分离株施加PZQ治疗压力8代，研究治疗压力下对PZQ不敏感寄生虫的可能选择情况。最后一代传代后，估计PZQ的ED50。所有对PZQ敏感的曼氏血吸虫分离株在所有传代过程中对PZQ均表现出稳定的敏感性（平均PZQ ED50 = 85 mg/kg）。7个对PZQ不敏感的曼氏血吸虫分离株中的2个（847和ER5）在1 - 2代传代中对PZQ表现出正常敏感性（尽管不是最后一代，且ED50没有下降趋势），而其余传代对该药物持续不敏感（平均PZQ ED50 = 217 mg/kg）。蠕虫的成熟度和性别与单个分离株在不同传代过程中药物ED50的变异性无关，这揭示了寄生虫的异质性。有限生命周期传代的治疗压力并未导致药物ED50显著增加。一些对PZQ不敏感的曼氏血吸虫分离株恢复到正常药物敏感状态的情况并不持久，且现场PZQ的治疗压力与实验室（无限制）的不同，这使得监测患者在现场对该药物的反应成为血吸虫病控制措施的一个组成部分。
