Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels

Álvarez, Luis Ignacio Ortega; Suárez, Gonzalo; Ceballos, Laura; Moreno, Laura; Cantón, Candela; Lifschitz, Adrián Luis; Maté, L.; Ballent, Mariana; Virkel, G.; Lanusse, Carlos

doi:10.1016/j.vetpar.2015.03.001

Cited by 25 publications

(23 citation statements)

References 54 publications

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“…On the other hand, exposure of the same isolates of C. elegans to IVM resulted in upregulation of a different set of P-gp genes [ 8 ]. Some studies on parasitic nematodes have reported increases in transcription of transporter genes following in vitro and in vivo exposure to IVM [ 12 , 16 , 26 ], whereas no transcriptional changes were observed in IVM-resistant H. contortus and Cooperia oncophora worms collected from animals treated with IVM compared to the worms collected from untreated control animals [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of ATP binding cassette transporter genes following exposure of Haemonchus contortus larvae to a high concentration of monepantel in vitro

et al. 2016

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BackgroundThere is some evidence that ATP binding cassette (ABC) transporters play a role in resistance to anthelmintics, particularly against macrocyclic lactones. Some anthelmintics, including ivermectin (IVM), have been shown to induce transcription of multiple ABC transporters in nematodes; however, the effects of monepantel (MPL) on transcription of these transporter genes has not been studied.MethodsLarvae of two MPL-susceptible isolates of Haemonchus contortus were exposed to MPL at two concentrations (2.5 and 250 μg/ml) for periods of 3, 6 and 24 h. Transcription levels of sixteen ABC transporter genes were measured at the end of the incubation periods. The consequences of MPL exposure were examined by measuring rhodamine-123 efflux from the larvae, and their sensitivity to subsequent treatment with IVM or levamisole.ResultsMultiple ABC transporter genes showed significantly higher transcription in both worm isolates following exposure to MPL at 250 μg/ml for 3, 6 or 24 h, particularly the P-glycoprotein (P-gp) genes pgp-11, pgp-12 and pgp-14. Of these, only pgp-11 maintained the elevated levels 24 h after the end of the drug exposure period. In contrast, there was only a single instance of low-level upregulation as a result of exposure to MPL at 2.5 μg/ml. Larvae exposed to MPL at 250 μg/ml showed an increased efflux of rhodamine-123 and a proportion of the larval population showed an ability to subsequently tolerate higher concentrations of IVM in migration assays. There was no increased tolerance to IVM following pre-exposure to MPL at 2.5 μg/ml.ConclusionsExposure of H. contortus larvae to 250 μg/ml MPL results in increased transcription of multiple transporter genes and increased R-123 efflux. The subsequent ability of a proportion of the larvae to tolerate IVM suggests a protective role of ABC transporters across different chemical entities. However, these observations were only made at a concentration of MPL well above that experienced by parasitic life stages in vivo, and hence their significance remains unclear.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1806-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Increased expression of ATP binding cassette transporter genes following exposure of Haemonchus contortus larvae to a high concentration of monepantel in vitro

et al. 2016

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“…the transcriptional level of transporter genes following in vivo (Lloberas et al, 2013;Xu et al, 1998b) and in vitro exposure to anthelmintic drugs (Raza et al, 2016a(Raza et al, , 2016bWilliamson et al, 2011;Xu et al, 1998a). However, other studies have reported no transporter transcriptional changes in nematodes collected from animals treated with IVM (Alvarez et al, 2015;Areskog et al, 2013). Williamson and Wolstenholme (2012) were able to quantify P-gp13 expression (reported in the manuscript as P-gp12 and P-gp14) by qPCR in the L3 stage of H. contortus.…”

Section: Accepted Manuscriptmentioning

confidence: 91%

“…In the first efficacy trial, parasite free Corriedale lambs (21.2 ± 3.1 kg, n= 6) were infected with an IVM-resistant H. contortus isolate (7000 L3/lamb) (artificial infection I). It has been previously demonstrated that IVM (0.2 mg/kg) failed to control this isolate, with reported efficacies of 42 to 50% (Alvarez et al, 2015). Thirty days after infection, lambs were orally treated with IVM (Ivomec®, Merial, Argentina) at the dose of 2 mg/kg (dose x 10) (Treatment I).…”

Section: Laboratory-selected Isolatementioning

confidence: 99%

Assessment of P-glycoprotein gene expression in adult stage of Haemonchus contortus in vivo exposed to ivermectin

Maté

Ballent

Cantón

et al. 2018

Veterinary Parasitology

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“…There is a strong relationship between the amount of drug reaching the target parasite and the induced anthelmintic effect. Thus, even for resistant worms, increasing drug exposure (by increasing the concentration, the time of exposure or both) may help recover high anthelmintic efficacy (Várady et al, 1996;Moreno et al, 2004;Barrère et al, 2012;Lloberas et al, 2015;Alvarez et al, 2015). The enhancement of drug systemic exposure will facilitate that higher drug concentrations reach the parasite location for a sufficient time to improve the antiparasitic effect, particularly against worms carrying resistance genes.…”

Section: Pharmacological Assessment Of Combinations Between Anthelminmentioning

confidence: 99%

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

Lanusse

Lifschitz

Álvarez

2015

Veterinary Parasitology

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Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels

Cited by 25 publications

References 54 publications

Increased expression of ATP binding cassette transporter genes following exposure of Haemonchus contortus larvae to a high concentration of monepantel in vitro

Increased expression of ATP binding cassette transporter genes following exposure of Haemonchus contortus larvae to a high concentration of monepantel in vitro

Assessment of P-glycoprotein gene expression in adult stage of Haemonchus contortus in vivo exposed to ivermectin

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

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