title: Experimental treatment of Neospora caninum-infected mice with the arylimidamide DB750 and the thiazolide nitazoxanide.
abstract: The cationic arylimidamide DB750 and the thiazolide nitazoxanide had been shown earlier to be effective against Neospora caninum tachyzoites in vitro with an IC(50) of 160nM and 4.23μM, respectively. In this study, we have investigated the effects of DB750 and nitazoxanide treatments of experimentally infected Balb/c mice, by applying the drugs either through the oral or the intraperitoneal route. In experiment 1, administration of DB750 (2mg/kg/day) and nitazoxanide (150mg/kg/day) started already 3 days prior to experimental infection of mice with 2×10(6) tachyzoites. Following infection, the drugs were further administrated daily for a period of 2 weeks, either orally or intraperitoneally. Intraperitoneal injection of DB750 was well tolerated by the mice, but treatment with nitazoxanide resulted in death of all mice within 3 days. Upon intraperitoneal application of DB750, the cerebral parasite load was significantly reduced compared to all other groups, while oral application of DB750 and nitazoxanide were not as effective, and resulted in significant weight loss. In experiment 2, mice were infected with 2×10(6) tachyzoites and at 2 weeks post-infection, DB750 (2mg/kg/day) was applied by intraperitoneal injections for 14 days. In the DB750-treated group, only 2 out of 12 mice succumbed to infection, compared to 7 out of 12 mice in the placebo-group. DB750 treatment also resulted in significantly reduced cerebral parasite burden, and reduced numbers of viable tachyzoites. Our data suggest that DB750 exerted its activity also after crossing the blood-brain barrier, and that this class of compounds could be promising for the control of N. caninum-associated disease.
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. karim.debache@vetsuisse.unibe.ch
authors.forename: Karim
authors.initials: K
authors.lastname: Debache
authors.forename: Christophe
authors.initials: C
authors.lastname: Guionaud
authors.forename: Christian
authors.initials: C
authors.lastname: Kropf
authors.forename: David
authors.initials: D
authors.lastname: Boykin
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000469:parasitology; D002460:Cell Line; D002522:Chlorocebus aethiops; D003048:Coccidiosis / Q000188:drug therapy*; D003049:Coccidiostats / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016054:DNA, Protozoan / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000469:parasitology; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D018688:Neospora / Q000187:drug effects*; D009574:Nitro Compounds; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014709:Vero Cells
chemical_list: D000578:Amidines; D003049:Coccidiostats; C561940:DB 750; D016054:DNA, Protozoan; D009574:Nitro Compounds; D011725:Pyridines; D013844:Thiazoles; C041747:nitazoxanide