Strohbusch M, Müller N, Hemphill A, Krebber R, Greif G, Gottstein B
Institute of Parasitology, University of Berne, Berne, Switzerland.
Parasitol Res. 2009 Jun;104(6):1335-43. doi: 10.1007/s00436-009-1328-x. Epub 2009 Feb 10.
C57BL/6 mice were infected with Neospora caninum tachyzoites during pregnancy, yielding a transplacental infection of developing fetuses. Subsequently, congenitally infected newborn mice were treated either once or three times with toltrazuril (or placebo) at a concentration of 31.25 mg compound per kg body weight. Both toltrazuril and placebo treatment had no negative effect on newborns, as noninfected treated pups developed normally without differences in mortality and morbidity to matching nontreated control animals. Already one application of toltrazuril was significantly (p < 0.01) able to delay the outbreak of neosporosis in newborn mice, when compared to placebo-treated infected controls. We found significantly higher proportion of surviving newborns in one-time-toltrazuril-treated and three-time-toltrazuril-treated groups (34% and 54%, respectively) when compared to one-time-placebo-treated and three-time-placebo-treated groups (14% and 30%, respectively). There was no significant difference (p = 0.2) in the proportion of surviving pups between one-time-toltrazuril and three-time-toltrazuril treatment. However, the number of diseased and Neospora-positive pups (46% and 47%, respectively) was markedly reduced after three-time-toltrazuril treatment compared to all other groups. Three-time-treatment also resulted in the highest antibody (IgG, IgG2a) response. Pharmacokinetic analyses using individual serum samples revealed that, although toltrazuril was absorbed and metabolized to toltrazuril sulfone by newborn mice, medicated animals exhibited an unexpected rapid turn-over (half-life time) of the compound. Toltrazuril and the metabolite were also found in brain tissues, indicating that passage of the blood-brain barrier occurred. In conclusion, we could show that three times treatment with toltrazuril had a high impact on the course of infection in congenitally N. caninum-infected newborn mice.
在孕期，将犬新孢子虫速殖子感染C57BL/6小鼠，导致发育中的胎儿发生经胎盘感染。随后，对先天性感染的新生小鼠以每千克体重31.25毫克化合物的浓度用托曲珠利（或安慰剂）进行一次或三次治疗。托曲珠利和安慰剂治疗对新生小鼠均无负面影响，因为未感染的治疗幼崽发育正常，在死亡率和发病率方面与未治疗的匹配对照动物无差异。与安慰剂治疗的感染对照相比，仅一次应用托曲珠利就能显著（p < 0.01）延迟新生小鼠新孢子虫病的爆发。我们发现，与一次安慰剂治疗组和三次安慰剂治疗组（分别为14%和30%）相比，一次托曲珠利治疗组和三次托曲珠利治疗组存活新生小鼠的比例显著更高（分别为34%和54%）。一次托曲珠利治疗组和三次托曲珠利治疗组存活幼崽的比例无显著差异（p = 0.2）。然而，与所有其他组相比，三次托曲珠利治疗后患病和新孢子虫阳性幼崽的数量（分别为46%和47%）明显减少。三次治疗还导致最高的抗体（IgG、IgG2a）反应。使用个体血清样本进行的药代动力学分析表明，尽管新生小鼠吸收了托曲珠利并将其代谢为托曲珠利砜，但用药动物体内该化合物的周转（半衰期）出乎意料地快。在脑组织中也发现了托曲珠利及其代谢物，表明发生了血脑屏障的通透。总之，我们可以证明，三次使用托曲珠利治疗对先天性感染犬新孢子虫的新生小鼠的感染进程有很大影响。
