Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep

Lifschitz, Adrián Luis; Entrocasso, C.; Álvarez, Luis Ignacio Ortega; Lloberas, Mercedes; Ballent, Mariana; Manazza, G.; Virkel, G.; Borda, Bernadett; Lanusse, Carlos

doi:10.1016/j.vetpar.2010.04.039

Cited by 56 publications

(33 citation statements)

References 38 publications

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“…With regard to manipulation of drug uptake kinetics, enhanced activity and efficacy of anthelmintic + Pgp inhibitor combinations has been demonstrated by Molento and Prichard (1999), Bartley et al (2009) andLifschitz et al (2010). Again, this has led a number of workers to recommend this as a strategy to deal with drug resistance Hugnet et al, 2007;Alvinerie et al, 2008;Lespine et al, 2008Lespine et al, , 2009.…”

Section: Use Of Drug Combinationsmentioning

confidence: 99%

Reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy?

Fairweather

2011

Veterinary Parasitology

135

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Section: Use Of Drug Combinationsmentioning

confidence: 99%

Reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy?

Fairweather

2011

Veterinary Parasitology

135

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“…As with the use of metabolic inhibitors, the combined use of anthelmintics plus Pgp inhibitors such as KTZ and verapamil has been advanced as a strategy to deal with drug resistance Hugnet et al 2007;Alvinerie et al 2008;. Enhanced activity and efficacy of such combinations has been demonstrated by Molento and Prichard (1999), Bartley et al (2009), andLifschitz et al (2010), for example.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2011

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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 cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) 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 CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 μM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ+NADPH+ TCBZ (15 μg/ml), or KTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO; 15 μg/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 TCBZ-resistant isolate. However, co-incubation with KTZ+ TCBZ, but more particularly KTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: in the syncytium, for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. 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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“…in naturally parasitized cattle tended to increase after their co-administration when loperamide was used as a P-gp modulator (Lifschitz et al, 2010a). Similarly, a significant increase in ivermectin efficacy against resistant nematodes in sheep, together with an enhancement on ivermectin systemic availability, was obtained after its combination with loperamide (Lifschitz et al, 2010b).…”

Section: Pharmacological Assessment Of Combinations Between Anthelminmentioning

confidence: 97%

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

Lanusse

Lifschitz

Álvarez

2015

Veterinary Parasitology

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Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep

Cited by 56 publications

References 38 publications

Reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy?

Reducing the future threat from (liver) fluke: realistic prospect or quixotic fantasy?

Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

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