title: Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole.
abstract: An in vivo study in the laboratory rat model was carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from combination treatment of triclabendazole (TCBZ) and the metabolic inhibitor, ketoconazole (KTZ). Rats were infected with the TCBZ-resistant Oberon isolate of F. hepatica and divided into 3 groups at 12 weeks post-infection. The first group was dosed orally with TCBZ at a dosage of 10mg/kg and KTZ at a dosage of 10mg/kg. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.). A second group of rats was treated with TCBZ alone (10mg/kg) and sacrificed at 96 h p.t. The third group acted as untreated controls. Surface changes were monitored by scanning electron microscopy (SEM). In flukes from the TCBZ+KTZ-treated group, the results showed a progressive and time-dependent increase in the level of disruption to the tegumental syncytium. Swelling, furrowing, blebbing and sloughing of the syncytium increased with time p.t. Another feature seen was a thick layer of tegumental shedding in some fluke samples at different times p.t. By comparison, flukes treated with TCBZ alone remained unaffected. The results demonstrated that the Oberon isolate is only sensitive to drug action in the presence of ketoconazole, indicating that combining triclabendazole with a metabolic inhibitor could be used to preserve the effectiveness of the drug against TCBZ-resistant populations of F. hepatica.
authors.affiliation: Parasite Therapeutics 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: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005210:Fasciola hepatica / Q000187:drug effects* / Q000302:isolation & purification / Q000648:ultrastructure; D005211:Fascioliasis / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008855:Microscopy, Electron, Scanning; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077682:Triclabendazole
chemical_list: D001562:Benzimidazoles; D000077682:Triclabendazole; D007654:Ketoconazole