title: Efficacy, safety and pharmacokinetics of 1,2,4-trioxolane OZ78 against an experimental infection with Fasciola hepatica in sheep.
abstract: The synthetic peroxide OZ78 is an effective flukicide in the rodent model, but the potential of OZ78 in target animals has not been studied to date. In the present study, OZ78 was administered at 50mg/kg orally and subcutaneously to sheep harbouring an experimental Fasciola hepatica infection and the efficacy, tolerability and pharmacokinetic profiles were monitored. OZ78 given orally or subcutaneously revealed no effect neither on faecal egg counts nor on worm burdens. Apart from significant subcutaneous swelling at the injection sites of most of the treated animals, no other treatment related adverse events occurred. OZ78 had no significant effect on any haematological, coagulation or clinical chemistry variables tested. Following oral administration, a mean C(max) of 45.8±13 μg/ml was reached after 1h. An estimated elimination half-life of 1.0 h and a mean AUC of 116.2±47 μg min/ml was calculated for the oral administration. Following subcutaneous treatment with OZ78 C(max) and t(max) were 13.7±6.1μg/ml and 0.9±0.4h, respectively. The α and β half-lives were 4.5±4.3 h and 56.5±36 h, respectively and the mean AUC was 219.1±74 μg min/ml. Further studies are needed to determine whether the excellent activity observed with OZ78 in the rat model can be translated into efficacy in larger mammals.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland. jennifer.keiser@unibas.ch
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.forename: Carla
authors.initials: C
authors.lastname: Kirchhofer
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vanhoff
authors.forename: Ronald
authors.initials: R
authors.lastname: Kaminsky
authors.forename: Nick
authors.initials: N
authors.lastname: Malikides
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005210:Fasciola hepatica / Q000254:growth & development*; D005211:Fascioliasis / Q000188:drug therapy / Q000469:parasitology / Q000662:veterinary*; D005243:Feces / Q000469:parasitology; D006207:Half-Life; D007279:Injections, Subcutaneous / Q000662:veterinary; D010270:Parasite Egg Count / Q000662:veterinary; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000469:parasitology*; D018709:Statistics, Nonparametric
chemical_list: D000871:Anthelmintics; C518172:OZ78 compound; D000218:Adamantane