Cattle nematodes resistant to macrocyclic lactones: Comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin

Lifschitz, Adrián Luis; Suárez, Víctor Humberto; Sallovitz, Juan Manuel; Cristel, S. L.; Imperiale, F.; Ahoussou, Sylvie; Schiavi, C.; Lanusse, Carlos

doi:10.1016/j.exppara.2010.01.009

Cited by 45 publications

(31 citation statements)

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“…Recent studies showed the increase of ivermectin efficacy against resistant nematode in sheep (Lifschitz et al 2010a) and cattle (Lifschitz et al 2010b) experimentally infected and also the enhance of ivermectin systemic concentration by the coadministration of loperamide, a Pgp modulator.…”

Section: Introductionmentioning

confidence: 99%

Weak phenotypic reversion of ivermectin resistance in a field resistant isolate of Haemonchus contortus by verapamil

et al. 2011

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Recent advances in anthelmintic resistant phenotype reversion by Pgp modulating drugs in ruminant nematodes indicate that this can be a useful tool to helminth control. The aim of the present study was to evaluate the efficacy of ivermectin (IVM) in combination with verapamil (VRP), in oil or water-based vehicle, against an IVM-resistant field isolate of Haemonchus contortus through a larval migration assay and experimental infection trial. In the in vitro assay was observed a phenotypic reversion of H. contortus resistance to ivermectin at a high concentration of VRP, increasing IVM efficacy from 53.1% to 94.3. In the in vivo trial, IVM + VRP demonstrated 36.02% efficacy compared to the 7.75% of IVM alone. The vehicle formulation showed no influence in efficacy. These are the first results demonstrating the effect of VRP as a partial IVM-resistance phenotype reverser in a field isolate of IVM-resistant H. contortus experimentally inoculated in sheep.

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Section: Introductionmentioning

confidence: 99%

Weak phenotypic reversion of ivermectin resistance in a field resistant isolate of Haemonchus contortus by verapamil

et al. 2011

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“…Regarding the sample preparation, most procedures described for MOX residue quantitation in plasma involve clean up steps using solid phase microextraction cartridges (SPME) 8,[11][12][13] and derivatization step. According to literature, the pharmacokinetic (PK) parameters of a veterinary drug vary according to the applied dose, animal species, type of animal and the application site, among others.…”

Section: Introductionmentioning

confidence: 99%

“…2, 2017 step. [8][9][10][11][12][13] Rarely are described analytical methods by using mass spectrometry as a detector for MOX.14 However, it is important to emphasize that analytical methods based on liquid chromatography coupled to mass spectrometry (HPLC-MS) are sufficiently sensitive and selective to quantify the compounds in very low amounts, not being necessary a derivatization step.Regarding the sample preparation, most procedures described for MOX residue quantitation in plasma involve clean up steps using solid phase microextraction cartridges (SPME) 8,11-13 and derivatization step. According to literature, the pharmacokinetic (PK) parameters of a veterinary drug vary according to the applied dose, animal species, type of animal and the application site, among others.…”

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Determination of Moxidectin in Serum by Liquid Chromatography-Tandem Mass Spectrometry and Its Application in Pharmacokinetic Study in Lambs

Baptista¹,

Fernandes²,

Gilaverte³

et al. 2016

Journal of the Brazilian Chemical Society

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The widespread use of moxidectin (MOX), a parasiticide used in the sheep breeding, has induced the parasite resistance in Brazilian farms. As a consequence, the farmers often increase the dose and frequency of drug utilization, and disregards safety of meat or milk. In order to establish adequate therapeutic treatment it is necessary to know the pharmacokinetics of the drug in the animal's body. Thus, high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for the determination of MOX in serum lamb. Serum samples were treated with acetonitrile to precipitate proteins. A clean up by dispersive extraction in solid phase (SPE-d), using primary/secondary amine (PSA) and C18 sorbents, followed by freezing was performed. Method validation presented precision (coefficient of variation) and accuracy (recovery%) between 1.7-6.7 and 80.0-107.3%, respectively. The limit of quantification (LOQ) of the method was 2.0 ng mL -1 and a linear response was obtained over a range of 2.0 to 100 ng mL -1 . This method was successfully applied to the determination of MOX in serum from suffolk lamb to evaluate the pharmacokinetic profile. Keywords: serum lamb, moxidectin, veterinary drug, pharmacokinetic, LC-MS/MS IntroductionThe infections with gastrointestinal nematodes have constituted major obstacle to the expansion of the sheep industry in Brazil. The gastrointestinal parasitism is associated with physiological changes in animals, such as bowel dysfunction and nutritional stress that result in decreased body condition, lower weight gain and death of animals. Among the most important parasites that affect sheep flocks we can highlight the Haemonchus contortus. The parasiticide agents allowed for controlling endo and ecto-parasites in sheep, the macrocyclic lactones, have been widely employed over the world because of its high efficiency and broad-spectrum activity.2 The moxidectin (MOX) (Figure 1), semisynthetic derivative of nemadectin, is a macrocyclic lactone obtained by the fermentation of Streptomyces cyanogriseus. 3 In the last decade MOX has emerged in sheep flocks in Brazil due to its efficacy against a wide variety of nematodes and arthropod parasites, even at extremely low doses. 4 However, similarly as occurred with other drugs, indiscriminate use of MOX could induce parasite resistance, affecting the efficiency of the drug.5 Actually, similarly to ivermectin and the benzimidazole, parasite resistance against MOX has been reported in Brazil. 6 As an action of parasite resistance control, alternatives have been studied in order to minimize the spread of animal diseases and the damage to the breeding and may be referred: correct management and grazing, proper sheep nutrition, selection of resistant animals, biological control, use of vaccines, herbal medicine and/or the use of techniques for assessing the degree of infection. 7Chromatographic methods for the determination of MOX in plasma from different species (alpacas, cattle, horses, pig, rabbit and s...

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“…Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8)(9)(10)(11)(12)(13), and they are involved in the tolerance of Caenorhabditis elegans (9,(14)(15)(16) and parasitic nematodes such as Haemonchus contortus or Cooperia oncophora (13,(17)(18)(19)(20) to MLs. In addition, mutation of the dyf-7 gene was associated with an IVM resistance phenotype in C. elegans and in H. contortus, leading to an abnormal dendritic morphology of amphid sensory neurons, as revealed by a dye-filling-defective phenotype (21).…”

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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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Cattle nematodes resistant to macrocyclic lactones: Comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin

Cited by 45 publications

References 43 publications

Weak phenotypic reversion of ivermectin resistance in a field resistant isolate of Haemonchus contortus by verapamil

Weak phenotypic reversion of ivermectin resistance in a field resistant isolate of Haemonchus contortus by verapamil

Determination of Moxidectin in Serum by Liquid Chromatography-Tandem Mass Spectrometry and Its Application in Pharmacokinetic Study in Lambs

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

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