Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole

Catherine G. Devine, Gerard Brennan, C.E. Lanusse, L.I. Alvarez, Alan Trudgett, Elizabeth Hoey, Ian Fairweather

Research output: Contribution to journalArticle

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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 10 mg/kg and KTZ at a dosage of 10 mg/kg. Flukes were recovered at 24, 48, 72 and 96h post-treatment (p.t.). A second group of rats was treated with TCBZ alone (10 mg/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. (C) 2010 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalVeterinary Parasitology
Volume177
Issue number3-4
DOIs
Publication statusPublished - 11 May 2011

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triclabendazole
Fasciola hepatica
ketoconazole
Ketoconazole
Trematoda
flukes
metabolic inhibitors
giant cells
Giant Cells
drugs
rats
Blister
dosage
in vivo studies

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Devine, Catherine G. ; Brennan, Gerard ; Lanusse, C.E. ; Alvarez, L.I. ; Trudgett, Alan ; Hoey, Elizabeth ; Fairweather, Ian. / Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole. In: Veterinary Parasitology. 2011 ; Vol. 177, No. 3-4. pp. 305-315.
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Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole. / Devine, Catherine G.; Brennan, Gerard; Lanusse, C.E.; Alvarez, L.I.; Trudgett, Alan; Hoey, Elizabeth; Fairweather, Ian.

In: Veterinary Parasitology, Vol. 177, No. 3-4, 11.05.2011, p. 305-315.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Enhancement of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica by co-treatment with ketoconazole

AU - Devine, Catherine G.

AU - Brennan, Gerard

AU - Lanusse, C.E.

AU - Alvarez, L.I.

AU - Trudgett, Alan

AU - Hoey, Elizabeth

AU - Fairweather, Ian

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N2 - 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 10 mg/kg and KTZ at a dosage of 10 mg/kg. Flukes were recovered at 24, 48, 72 and 96h post-treatment (p.t.). A second group of rats was treated with TCBZ alone (10 mg/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. (C) 2010 Elsevier B.V. All rights reserved.

AB - 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 10 mg/kg and KTZ at a dosage of 10 mg/kg. Flukes were recovered at 24, 48, 72 and 96h post-treatment (p.t.). A second group of rats was treated with TCBZ alone (10 mg/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. (C) 2010 Elsevier B.V. All rights reserved.

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M3 - Article

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JO - Veterinary Parasitology

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SN - 0304-4017

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