title: Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole.
abstract: An in vivo study in the laboratory rat model has been carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from co-treatment with triclabendazole (TCBZ) and ketoconazole (KTZ), a cytochrome P450 inhibitor. Rats were infected with the triclabendazole-resistant Oberon isolate of F. hepatica, dosed orally with triclabendazole at a dosage of 10mg/kg live weight and ketoconazole at a dosage of 10mg/kg live weight. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.) and changes to fluke ultrastructure were assessed using transmission electron microscopy (TEM). Results showed an increase in the severity of changes to the fluke ultrastructure with time p.t. Swelling of the basal infolds and the associated mucopolysaccharide masses became more severe with time. Golgi complexes, if present, were greatly reduced in size and number by 96 h p.t., and sub-tegumental flooding was seen from the 72 h time-period onwards. Some sloughing of the tegumental covering over the spines was observed at 96 h p.t. The results demonstrated that the Oberon isolate is more sensitive to TCBZ action in the presence of KTZ than to TCBZ alone, reinforcing the idea that altered drug metabolism is involved in the resistance mechanism. Moreover, they support the concept that TCBZ+inhibitor combinations (aimed at altering drug pharmacokinetics and potentiating the action of TCBZ) could be used in the treatment of TCBZ-R populations of F. hepatica.
authors.affiliation: Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Devine
authors.forename: G P
authors.initials: GP
authors.lastname: Brennan
authors.forename: C E
authors.initials: CE
authors.lastname: Lanusse
authors.forename: L I
authors.initials: LI
authors.lastname: Alvarez
authors.forename: A
authors.initials: A
authors.lastname: Trudgett
authors.forename: E
authors.initials: E
authors.lastname: Hoey
authors.forename: I
authors.initials: I
authors.lastname: Fairweather
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance / Q000187:drug effects*; D004357:Drug Synergism; D005210:Fasciola hepatica / Q000187:drug effects* / Q000648:ultrastructure; D005211:Fascioliasis / Q000188:drug therapy; D007654:Ketoconazole / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D046529:Microscopy, Electron, Transmission; D051381:Rats; D000077682:Triclabendazole
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000871:Anthelmintics; D001562:Benzimidazoles; D000077682:Triclabendazole; D007654:Ketoconazole