Field trial assessment of ivermectin pharmacokinetics and efficacy against susceptible and resistant nematode populations in cattle

Cantón, Candela; Cantón, Lucila; Dominguez, María Paula; Moreno, Laura; Lanusse, Carlos; Álvarez, Luis Ignacio Ortega; Ceballos, Laura

doi:10.1016/j.vetpar.2018.05.007

Cited by 17 publications

(17 citation statements)

References 33 publications

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“…The route of administration also has a significant effect on the pharmacokinetics of endectocides [ 60 ]. Ivermectin pharmacokinetics studies have been conducted in cattle to compare subcutaneous and oral routes of administration [ 16 , 61 ]. One study showed that ivermectin injected subcutaneously in cattle was effective against An.…”

Section: Introductionmentioning

confidence: 99%

The effect of cattle-administered ivermectin and fipronil on the mortality and fecundity of Anopheles arabiensis Patton

2021

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Background Malaria control primarily depends on two vector control strategies: indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs). Both IRS and LLIN target indoor-biting mosquitoes. However, some of the most important malaria vectors have developed resistance against the chemical compounds used in IRS and LLINs. Insecticide-induced behavioural changes in vectors, such as increased outdoor feeding on cattle and other animals, also limit the effectiveness of these strategies. Novel vector control strategies must therefore be found to complement IRS and LLINs. A promising tool is the use of cattle-applied endectocides. Endectocides are broad-spectrum systemic drugs that are effective against a range of internal nematodes parasites and blood-feeding arthropods. The aim of this study was to investigate the effect of two endectocide drugs, injectable ivermectin and topical fipronil, on the survival and fecundity of zoophilic Anopheles arabiensis. Methods Laboratory-reared mosquitoes were allowed to feed on cattle treated with either injectable ivermectin (0.2 mg/kg), topical fipronil (1.0 mg/kg) or saline (control) on days 0, 1, 4, 7, 13, 21 and 25 post-treatment, and mortality and egg production were recorded daily. Results Compared to controls, the mortality of An. arabiensis increased by 3.52- and 2.43-fold with injectable ivermectin and topical fipronil, respectively. The overall fecundity of mosquitoes that fed on both ivermectin- and fipronil-treated cattle was significantly reduced by up to 90 and 60%, respectively, compared to the control group. The effects of both drugs attenuated over a period of 3 weeks. Injectable ivermectin was more effective than topical fipronil and increased mosquito mortality by a risk factor of 1.51 higher than fipronil. Similarly, both drugs significantly reduced the fecundity of An. arabiensis. Conclusions This study demonstrates that injectable ivermectin and topical fipronil are able to suppress An. arabiensis density and could help to reduce outdoor malaria transmission. Data from the present study as well as from other similar studies suggest that current-generation endectocides have a limited duration of action and are expensive. However, new-generation, sustained-release formulations of ivermectin have a multi-week, high mortality impact on vector populations, thus holding promise of an effective reduction of outdoor malaria transmission. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

The effect of cattle-administered ivermectin and fipronil on the mortality and fecundity of Anopheles arabiensis Patton

2021

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“…As shown in earlier studies ( Oksanen et al, 1995 ; Lespine et al, 2005 ; Lloberas er al., 2012; Leathwick and Miller, 2013 ; Macintosh et al, 2014 ; Cocquyt et al, 2016 ; Canton et al, 2018 ; Fazzio et al, 2019 ), the plasma concentrations of ML anthelmintics are generally higher following subcutaneous administration than following oral or pour-on administration ( Fig. 1 ; Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…The data suggests, therefore, that efficacy against Cooperia is likely to be associated with routes of administration that result in high concentrations of drug in the intestinal contents, rather than the mucosa. A relationship between drug concentrations in the worms and that in the intestinal contents has been hypothesised previously based on the greater efficacy of orally administered MLs over other routes of administration ( Leathwick and Miller, 2013 ; Leathwick et al, 2016 ; Saumell et al, 2017 ; Canton et al, 2018 ), assuming an absence of licking. This conclusion is supported by data from registration trials for ivermectin ( Benz et al, 1989 ) in which efficacy against adult C .…”

Section: Discussionmentioning

confidence: 99%

“…Since concentration gradient is a major determinant of drug accumulation in the worms ( Alvarez et al, 2007 ), it follows that differences in drug concentrations within the worms, and the resultant differences in efficacy, reflect the levels of drug in the tissues surrounding the parasites ( Alvarez et al, 2000 ; Mottier et al, 2006 ; Lloberas et al, 2012 ). Based on the greater efficacy of oral delivery over SC and pour-on administration against many parasites ( Gopal et al, 2001 ; Pomroy et al, 2004 ; Leathwick and Miller, 2013 ; Saumell et al, 2017 ; Canton et al, 2018 ), and the higher ML concentrations measured in the intestinal fluids ( Lloberas et al, 2012 ) it has been assumed that most parasites accumulate drug from the intestinal content ( Lifschitz et al, 2017 ). However, in this study it appears that for O .…”

Section: Discussionmentioning

confidence: 99%

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Route of administration influences the concentration of ivermectin reaching nematode parasites in the gastrointestinal tract of cattle

Leathwick

Miller

Waghorn

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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An animal trial was conducted to measure the concentrations of ivermectin occurring in abomasal and small intestinal contents and mucosa, and in the target parasites ( Ostertagia ostertagi and Cooperia oncophora ) following administration by subcutaneous, oral and pour-on routes. Twenty-five steers were infected with ivermectin-resistant isolates of O . ostertagi and C . oncophora and following patency randomly allocated to 3 treatment groups of 7 and 1 untreated control group of four. On day 0, animals in the treatment groups were administered ivermectin via the oral, injectable or pour-on routes. On days 1, 2, 3, 4, 5, 6 and 8, blood samples were collected from all live animals, one animal from each treatment group was euthanised and the abomasum and small intestine recovered. Control animals were euthanised on each of days 4, 5, 6 and 8. Samples of gastrointestinal tract organs, their contents, mucosa and parasites were collected and assayed for ivermectin concentration using HPLC. The highest plasma concentrations occurred following subcutaneous administration. In the gastrointestinal contents the highest levels occurred following oral administration, although one high value occurred following pour-on administration, which was attributed to self-licking by the treated animal. The lowest GI content levels followed subcutaneous injection. Ivermectin concentrations in the gastrointestinal mucosa were highest following subcutaneous injection. Drug levels in the abomasal parasite O . ostertagi were most closely correlated with levels in the abomasal mucosa whereas levels in the intestinal C . oncophora were most closely correlated with those in the intestinal contents. Thus, the maximun levels of drug reached C . oncophora in the small intestine following oral administration. In contrast, the highest levels of ivermectin in O . ostertagi followed subcutaneous injection. Therefore, route of administration is likely to influence the exposure to ivermectin for different parasite species.

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“…All farms (Farms 1, 2 and 3) had a grazing system of meat production representative of Argentina bovine production. The resistance status of the nematode population characteristic of each farm was previously determined by the faecal egg count reduction test (FECRT) ( Canton et al, 2019 ). In this way, the study included two farms with a predominance of IVM and RBZ-resistant nematode population (Farms 1 and 3) and one farm with only an IVM-resistant nematode population (Farm 2).…”

Section: Methodsmentioning

confidence: 99%

Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes

Cantón

Lifschitz

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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The goal of the current work was to perform an integrated evaluation of monepantel (MNP) pharmacokinetics (PK) and pharmacodynamics, measured as anthelmintic efficacy, after its oral administration to calves naturally infected with GI nematodes resistant to ivermectin (IVM) and ricobendazole (RBZ) on three commercial farms. On each farm, forty-five calves were randomly allocated into three groups (n = 15): MNP oral administration (2.5 mg/kg); IVM subcutaneous (SC) administration (0.2 mg/kg); and RBZ SC administration (3.75 mg/kg). Eight animals from the MNP treated group (Farm 1) were selected to perform the PK study. Drug concentrations were measured by HPLC. The efficacy was determined by the faecal egg count reduction test (FECRT). MNP and MNP-sulphone (MNPSO 2 ) were the main analytes recovered in plasma. MNPSO 2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO 2 metabolite (96.8 ± 29.7 ng/mL and 9220 ± 1720 ng h/mL) compared to MNP (21.5 ± 4.62 ng/mL and 1709 ± 651 ng h/mL). The MNPSO 2 AUC value was 6-fold higher compared to the parent drug. Efficacies of 99% (Farm 1), 96% (Farm 2) and 98% (Farm 3) demonstrated the high activity of MNP (P < 0.05) against GI nematodes resistant to IVM (reductions between 27 and 68%) and RBZ (overall efficacy of 75% on Farm 3). While IVM failed to control Haemonchus spp. and Cooperia spp., and RBZ failed to control Coooperia spp. and Ostertagia spp., MNP achieved 100% efficacy against Haemonchus spp., Cooperia spp. and Ostertagia spp. However, a low efficacy of MNP against Oesophagostomum spp. (efficacies ranging from 22 to 74%) was observed. In conclusion, oral treatment with MNP should be considered for dealing with IVM and benzimidazole resistant nematode parasites in cattle. The work described here reports for the first time an integrated assessment of MNP pharmaco-therapeutic features and highlights the need to be considered as a highly valuable tool to manage nematode resistant to other chemical families.

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Field trial assessment of ivermectin pharmacokinetics and efficacy against susceptible and resistant nematode populations in cattle

Cited by 17 publications

References 33 publications

The effect of cattle-administered ivermectin and fipronil on the mortality and fecundity of Anopheles arabiensis Patton

The effect of cattle-administered ivermectin and fipronil on the mortality and fecundity of Anopheles arabiensis Patton

Route of administration influences the concentration of ivermectin reaching nematode parasites in the gastrointestinal tract of cattle

Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes

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