Toltrazuril treatment of congenitally acquired Neospora caninum infection in newborn mice.
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.
Strohbusch
M
M
Institute of Parasitology, University of Berne, Berne, Switzerland.
Müller
N
N
Hemphill
A
A
Krebber
R
R
Greif
G
G
Gottstein
B
B
D000818:Animals; D000831:Animals, Newborn; D000913:Antibodies, Protozoan / Q000097:blood; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001923:Brain Chemistry; D003048:Coccidiosis / Q000188:drug therapy* / Q000382:microbiology*; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018688:Neospora / Q000187:drug effects* / Q000276:immunology; D011247:Pregnancy; D044967:Serum / Q000737:chemistry; D016019:Survival Analysis; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000913:Antibodies, Protozoan; D000981:Antiprotozoal Agents; D014227:Triazines; C036670:toltrazuril