Toltrazuril treatment of congenitally acquired Neospora caninum infection in newborn mice

Abstract

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 placebotreated infected controls. We found significantly higher proportion of surviving newborns in one-time-toltrazuriltreated and three-time-toltrazuril-treated groups (34% and 54%, respectively) when compared to one-time-placebotreated 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-timetoltrazuril and three-time-toltrazuril treatment. However, the number of diseased and Neospora-positive pups (46% and 47%, respectively) was markedly reduced after three-timetoltrazuril treatment compared to all other groups. Threetime-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 turnover (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.

Study on the use of toltrazuril to eliminate Neospora caninum in congenitally infected lambs born from experimentally infected ewes

“…Toltrazuril and its metabolites have been shown in a number of studies to be effective against tachzyoites (Kritzner et al, 2002;Strohbusch et al, 2008). Using a similar approach to that of the present study with a murine model, Strohbusch et al (2009) demonstrated that the treatment of neonatal mice with toltrazuril reduced, but did not eliminate, the infection. Although not specifically stated, presumably both tachyzoites and bradyzoites would have been present in these treated neonatal mice.…”

“…Toltrazuril, a symmetrical triazinone, is metabolized into ponazuril (toltrazuril sulfone). Both toltrazuril and ponazuril are effective against a broad spectrum of cyst-forming and non-cyst-forming apicomplexan protozoa (Haberkorn, 1996) including positive effects against N. caninum in vitro (Darius et al, 2004;Strohbusch et al, 2008) and in vivo, both in mice (Strohbusch et al, 2009) as well as in experimentally and naturally infected calves (Haerdi et al, 2006;Kritzner et al, 2002). However, in order for toltrazuril to reach its full effectiveness in clearing N. caninum infection, one study has shown that a supportive T cell-immune response is necessary (Ammann et al, 2004).…”

Neosporosis in animals—The last five years

“…However, interesting experimental studies that may result in an option for chemotherapeutic control at a later stage have been conducted. An effect of toltrazuril and its derivative ponazuril on tachyzoites on N. caninum has been shown in vitro and in vivo in calves (Strohbusch et al, 2009). In calves treated with ponazuril, the parasite was no longer detectable in the brain and other organs.…”

Effects of Neospora caninum on reproductive performance and the efficacy of treatment with a combination of sulphadiazine-trimethoprim and toltrazuril: a longitudinal field study

“…The calf may be chronically infected, with or without clinical symptoms (Anderson et al 2000;Dubey and Schares 2006) or Neospora free (Orozco et al 2012). Some experimental studies have investigated the importance of chemotherapeutic agents for the control of Neospora infections, such as toltrazuril and ponazuril (Kritzner et al 2002;Strohbusch et al 2009), monensin (VanLeeuwen et al 2010a, and a combination of sulphadiazine-trimethoprim and toltrazuril (Cuteri et al 2005).…”