Adult triclabendazole-resistant<i>Fasciola hepatica</i>: morphological changes in the tegument and gut following<i>in vivo</i>treatment with artemether in the rat model

O'Neill, J.F.; Johnston, R.C.; Halferty, L.; Brennan, Gerard; Keiser, Jennifer; Fairweather, Ian

doi:10.1017/s0022149x09344934

Cited by 32 publications

(33 citation statements)

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“…A similar observation has been made by O'Neill et al (2009). The severe disruption of the tegumental syncytium and subtegumental tissues might contribute to the efficacy of this particular synthetic peroxide against F. hepatica ( Keiser et al 2006Keiser et al b, 2007Keiser and Morson, 2008 b).…”

Section: Discussionmentioning

confidence: 56%

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Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

et al. 2009

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Adult Fasciola hepatica were incubated for 48 h in vitro in the synthetic peroxide, OZ78 at a concentration of 100 mg/ml and then prepared for scanning and transmission electron microscopy. There was limited disruption to the external fluke surface, with only slight swelling and blebbing of the interspinal tegument in the midbody and ventral tail regions. By contrast, significant disruption was observed to the ultrastructure of the tegument and subtegumental tissues. There was severe swelling of the basal infolds in the tegumental syncytium and the flooding spread internally to affect the subtegumental tissues. In the tegumental system, there was swelling of the cisternae of granular endoplasmic reticulum and of the mitochondria, with the latter showing signs of breaking down. Autophagic vacuoles and lipid droplets were present and the synthesis of tegumental secretory bodies was much reduced. The gastrodermal cells were severely affected, with swelling and degeneration of the mitochondria and the presence of autophagic vacuoles and lipid droplets. The granular endoplasmic reticulum was swollen and vesiculated and the cells contained few secretory bodies. Both the vitelline and testis follicles showed evidence of extensive cellular disruption and degeneration. This study confirms previous data indicating the potential flukicidal activity of OZ78.

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Section: Discussionmentioning

confidence: 56%

“…In a separate in vivo study on F. hepatica involving artemether, the gut was consistently more severely affected than the tegument, lending support to the notion of oral uptake of the artemisinin compounds (O'Neill et al 2009). In the present study, the gut was severely disrupted and this would make the condition of the fluke worse.…”

Section: Discussionmentioning

confidence: 64%

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

et al. 2009

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“…Co-incubation of MTZ with TCBZ resulted in an accumulation of secretory bodies just below the apical plasma membrane. This, too, is indicative of a stress response by the fluke and is a common reaction to treatment with other fasciolicidal drugs, as it serves as a survival mechanism to replace damaged tegument (Fairweather et al 1986;Stitt and Fairweather 1994;Buchanan et al 2003;Meaney et al 2004Meaney et al , 2005Meaney et al , 2007McConville et al 2006McConville et al , 2007McConville et al , 2008McConville et al , 2009bMcKinstry et al 2007McKinstry et al , 2009Halferty et al 2009a, b;O'Neill et al 2009;Toner et al 2009Toner et al , 2010. Swelling of the mitochondria and cisternae of GER was exacerbated but, more significantly, the production of secretory bodies in the tegumental cells appeared to be affected, as evidenced by the reduced size of the Golgi complexes and the reduced number of secretory bodies in the cells.…”

Section: Discussionmentioning

confidence: 97%

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2010

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 microM), then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM); MTZ+NADPH+TCBZ (15 microg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 microg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than triclabedazole-resistant isolate. However, co-incubation with MTZ+TCBZ, but more particularly MTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own, with severe swelling of the basal infolds and mucopolysaccharide masses in the syncytium, accompanied by a reduction in numbers of secretory bodies. The synthesis and production of secretory bodies in the tegumental cells was severely affected as well. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes, and this process may play a role in the development of drug resistance.

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“…This finding might be explained by the independent mechanism of action of the drugs. While artemether enters the parasite through oral ingestion and causes substantial disruption to the gut, triclabendazole mainly affects the tegument (29,35). Furthermore, artemether and OZ78 also act against triclabendazole-resistant F. hepatica (22).…”

Section: Discussionmentioning

confidence: 99%

In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

Duthaler

Smith

Keiser

2010

Antimicrob Agents Chemother

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Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P ‫؍‬ 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.

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Adult triclabendazole-resistantFasciola hepatica: morphological changes in the tegument and gut followingin vivotreatment with artemether in the rat model

Cited by 32 publications

References 55 publications

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

Electron microscopical study to assess thein vitroeffects of the synthetic trioxolane OZ78 against the liver fluke,Fasciola hepatica

Potentiation of triclabendazole sulphoxide-induced tegumental disruption by methimazole in a triclabendazole-resistant isolate of Fasciola hepatica

In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

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