Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression

Lloberas, Mercedes; Álvarez, Luis Ignacio Ortega; Entrocasso, C.; Virkel, G.; Ballent, Mariana; Maté, L.; Lanusse, Carlos; Lifschitz, Adrián Luis

doi:10.1016/j.ijpddr.2012.11.001

Cited by 69 publications

(78 citation statements)

References 42 publications

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“…These results are in full agreement with data from previous in vivo studies, which showed that MOX efficacy is maintained at higher levels than is IVM efficacy as ML resistance develops, as well as in vitro studies on drug-resistant parasitic nematodes, where MOX was more potent than IVM, while EPR was the least potent drug, displaying the highest resistance ratio compared to IVM and MOX (35,(43)(44)(45)(46)(47)(48)(49)(50)(51). These similarities with the ML-selected C. elegans strains clearly show that the model of drug selection pressure in C. elegans can be relevant to studies of the adaptation of parasitic nematodes to ML treatment in the field.…”

Section: Discussionsupporting

confidence: 91%

“…Since PGP6 is expressed in the amphids, its overexpression could help protect the nematodes from the effects of ML on extrapharyngeal neurons associated with the amphids. In addition, our results show the constitutive overexpression of Pgp2, Pgp9, and Pgp11 after both IVM and MOX selection, in accordance with the association of their homologs in ML resistance in H. contortus, Teladorsagia circumcincta, and Parascaris equorum (13,43,44,58,59). Generally, a similar pattern of expression of the regulated genes was found in the IVM-selected and the MOX-selected strains, in agreement with the similar transcriptional profiles of the multidrug resistance-associated proteins (MRPs) in C. elegans (8) and ABC transporters in C. oncophora (10) following exposure to IVM and MOX.…”

Section: Discussionsupporting

confidence: 85%

“…Data from natural populations of nematodes, and from artificial drug selection, suggest that MOX resistance generally develops more slowly than IVM resistance and that MOX efficacy is maintained at higher levels than is IVM efficacy as ML resistance develops (24)(25)(26)(27)(28)(40)(41)(42)(43). In order to compare the impacts of drug selection with either IVM or MOX on the development of tolerance in nematodes, we generated a MOX-selected strain of the model nematode C. elegans, which was compared with an IVM-selected C. elegans strain described previously (11).…”

Section: Discussionmentioning

confidence: 99%

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Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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“…As can be seen in Table 2, this anthelmintic showed the highest effectiveness rate (stand-alone) in five studies involving sheep (CUNHA et al, 1998;THOMAZ-SOCCOL et al, 2004;CEZAR et al, 2010;LIMA et al, 2010b;SCZESNY-MORAES et al, 2010) and in three studies involving goats (AHID et al, 2007; RODRIGUES et al, 2007; LIMA et al, 2010b). Although its mechanism of action is similar to that of ivermectin, several authors around the world have observed the greater effectiveness of moxidectin in strains resistant to ivermectin (BARNES et al, 2001;VICKERS et al, 2001;LLOBERAS et al, 2013). Prichard et al (2012) ascribed the difference in the effectiveness of these two antiparasitics to different interactions in glutamate-gated ion channels where they act, and to different levels of expression of ABC proteins.…”

Section: Developments In Research and The Effectiveness Of Anthelmintmentioning

confidence: 95%

“…Prichard et al (2012) ascribed the difference in the effectiveness of these two antiparasitics to different interactions in glutamate-gated ion channels where they act, and to different levels of expression of ABC proteins. However, these proteins can cause cross-resistance between the two anthelmintics, owing to an overexpression of P-glycoprotein in response to the ordinary use of ivermectin, which may interfere in the effectiveness of moxidectin (LLOBERAS et al, 2013). This may explain the low effectiveness of moxidectin found in recent studies in Brazil (BUZZULINI et al, 2007;ROSALINSKI-MORAES et al, 2007;VERÍSSIMO et al, 2012;OLIVEIRA et al, 2014), where ivermectin is widely used.…”

Section: Developments In Research and The Effectiveness Of Anthelmintmentioning

confidence: 99%

Overview of anthelmintic resistance of gastrointestinal nematodes of small ruminants in Brazil

Salgado

Santos

2016

Rev. Bras. Parasitol. Vet.

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Frequent and inappropriate use of all classes of antiparasitic drugs in small ruminants has led to failures in their effectiveness, culminating in a global problem of anthelmintic resistance. Brazil stands out as one of the world's leaders in publications about anthelmintic resistance, and for having the most numerous reports of this resistance in small ruminants in the Americas. These studies have involved mainly the fecal egg count reduction test (FECRT) and its correlation with field management practices. In vivo effectiveness testing is conducted in areas where livestock is of greater economic significance, e.g., in the South (sheep) and Northeast (goats), or is important for research and economic centers, such as the Southeast (sheep). The most widely studied species is sheep, for which the widest range of drugs is also evaluated. Despite significant advances achieved in molecular research, laboratory analyses should include knowledge about the reality in the field so that they can become feasible for the producer. Moreover, molecular studies can be underpinned by the analysis of field studies, such as the maintenance of antiparasitic effectiveness over time and the mechanisms involved in this process.Keywords: Small ruminants, anthelmintic resistance, sheep, goat, gastrointestinal nematodes. ResumoO uso frequente e inapropriado de todas as classes de antiparasitários em pequenos ruminantes levou a falhas de eficácia, culminando na problemática global de resistência anti-helmíntica. O Brasil destaca-se como sendo um dos pioneiros nas publicações com resistência anti-helmíntica no mundo e por ter o maior número de relatos em pequenos ruminantes na América. Essas pesquisas envolvem principalmente o teste da redução da contagem de ovos nas fezes (TRCOF) e sua correlação com as práticas de manejo utilizadas no campo. Os estudos de testes de eficácia in vivo localizam-se em áreas onde há maior importância dos rebanhos como nas Regiões Sul (ovinos) e Nordeste (caprinos), ou com importância em polos de pesquisa e econômicos, como a região Sudeste (ovinos). Ovina é a espécie mais estudada e com maior gama de drogas avaliadas. Mesmo com grande avanço em pesquisas moleculares, as análises laboratoriais devem envolver o conhecimento da realidade do campo para que possam se tornar viáveis ao produtor. Além disso, a análise dos estudos de campo pode nortear estudos moleculares como, por exemplo, a manutenção da eficácia das drogas ao longo dos anos e os mecanismos envolvidos em tal processo.

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Drug Resistance in Nematodes

Prichard¹

2017

Antimicrobial Drug Resistance

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Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression

Cited by 69 publications

References 42 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Overview of anthelmintic resistance of gastrointestinal nematodes of small ruminants in Brazil

Drug Resistance in Nematodes

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