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      Assessment of the insecticidal activity of afoxolaner against Aedes aegypti in dogs treated with NexGard ® Translated title: Évaluation de l'activité insecticide de l'afoxolaner contre Aedes aegypti chez les chiens traités avec NexGard ®

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          Abstract

          Twelve healthy dogs were studied in this parallel group, blinded, randomised, and negative controlled efficacy study. On Day -1, the 12 dogs included were ranked within sex in descending order of individual pre-treatment (Day -5) fed mosquito counts and randomly allocated by blocks of two dogs to the untreated control group or the afoxolaner-treated group. NexGard ® (Merial, now part of Boehringer Ingelheim Animal Health) was administered orally on Day 0 in accordance with the European label instructions. On Days 1, 7, 14, 21 and 28, all dogs were exposed for a duration of 1 hour to 50 ± 5 unfed Aedes aegypti females. After each exposure, mosquitoes were collected after 1 hour and assessed for viability during collection and at 24 ± 2 hours. The arithmetic (and geometric) mean values of live fed mosquito counts at 24 hours after the exposure periods for the negative control group ranged from 33.7 (32.3) to 49.8 (49.7), indicating that this was a vigorous mosquito strain. There was no significant difference between control and treated groups in the number of live and fed mosquitoes at each 1 hour post-exposure collection time. Based on arithmetic and geometric mean values at 24 hours after each exposure, significantly fewer live fed mosquitoes were recorded in the treated group, compared to the negative control group, throughout the study ( p < 0.001). The afoxolaner insecticidal efficacy against A. aegypti varied from 98% (Day 2) to 75.3% (Day 29) based on arithmetic means, and 98.7% (Day 2) to 89.8% (Day 29) based on geometric means.

          Translated abstract

          Douze chiens en bonne santé ont été étudiés dans cette étude d'efficacité en aveugle, en groupes parallèles et avec contrôles négatifs. Au jour -1, les 12 chiens inclus ont été classés par sexe par ordre décroissant de prétraitement individuel (jour -5) de comptage de moustiques nourris et répartis au hasard par blocs de deux chiens, en groupe témoin non traité et en groupe traité par afoxolaner. Du NexGard ® (Merial, maintenant un membre de Boehringer Ingelheim Animal Health) a été administré par voie orale au jour 0 conformément aux instructions dela notice européenne. Aux jours 1, 7, 14, 21 et 28, tous les chiens ont été exposés pendant une durée de 1 heure à 50 ± 5 Aedes aegypti femelles à jeun. Une heure après chaque exposition, les moustiques ont été recueillis et leur viabilité a été évaluée à la collecte et après 24 ± 2 heures. Les valeurs moyennes arithmétiques (et géométriques) du nombre de moustiques vivants et nourris 24 heures après les périodes d'exposition pour le groupe témoin négatif variaient de 33,7 (32,3) à 49,8 (49,7), ce qui indique une bonne viabilité de la souche de moustiques. Il n'y avait pas de différence significative entre les groupes témoins et les groupes traités dans le nombre de moustiques vivants et nourris à chacune des collectes à 1 heure post-exposition. Sur la base des valeurs moyennes géométriques et arithmétiques, à 24 heures après chaque exposition, des nombres significativement plus petits de moustiques nourris et vivants ont été enregistrés dans le groupe traité par rapport au groupe témoin non traité pendant toute l'étude ( p < 0,001). L'efficacité insecticide de l'afoxolaner contre A. aegypti variait de 98 % (jour 2) à 75,3 % (jour 29) sur la base de moyennes arithmétiques, 98,7 % (jour 2) à 89,8 % (jour 29) sur la base de moyennes géométriques.

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          Most cited references 14

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          World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) second edition: guidelines for evaluating the efficacy of parasiticides for the treatment, prevention and control of flea and tick infestations on dogs and cats.

          These second edition guidelines, updated from the 2007 version (Marchiondo et al., 2007), are intended to assist the planning and conduct of laboratory and clinical studies to assess the efficacy of ectoparasiticides applied to dogs or cats for the purpose of treating, preventing and controlling flea and tick infestations. Major revisions to this second edition include guidelines on the assessment of systemic flea and tick products, an update of the geographical distribution of the common fleas and ticks species on dogs and cats, determination of flea and tick efficacy based on geometric versus arithmetic means with respect to geographic regulatory agencies, modification of tick categorization in the assessment of efficacy, expanded guidelines on repellency and anti-feeding effects, enhanced practical field study guidance, and considerations on the ranges of flea and ticks for infestations in laboratory studies. The term ectoparasiticide includes insecticidal and acaricidal compounds, as well as insect growth regulators. The range of biological activities from animal treatment that are considered include: repellency and anti-feeding effects, knockdown, speed of kill, immediate and persistent lethal effects, and interference with egg fertility and subsequent development of off-host life cycle stages. Information is provided on the selection of animals, dose determination, dose confirmation and field studies, record keeping, interpretation of results and animal welfare. These guidelines are also intended to assist regulatory authorities involved in the approval and registration of new topical or systemic ectoparasiticides, and to facilitate the worldwide adoption of harmonized procedures.
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            Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

            Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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              The intravenous and oral pharmacokinetics of afoxolaner used as a monthly chewable antiparasitic for dogs.

              The pharmacokinetics of afoxolaner in dogs was evaluated following either intravenous or after oral administration of NEXGARD(®), a soft chewable formulation. Afoxolaner is a member of one of the newest classes of antiparasitic agents, known as antiparasitic isoxazolines. The soft chewable formulation underwent rapid dissolution, and afoxolaner was absorbed quickly following oral administration of the minimum effective dose of 2.5mg/kg, with maximum plasma concentrations (Cmax) of 1,655 ± 332 ng/mL observed 2-6h (Tmax) after treatment. The terminal plasma half-life was 15.5 ± 7.8 days, and oral bioavailability was 73.9%. Plasma concentration-versus-time curves fit a 2-compartment model and increased proportionally with dose over the oral dose range of 1.0-4.0mg/kg, and over the oral dose range from 1.0 to 40 mg/kg. Following an intravenous dose of 1mg/kg, the volume of distribution (Vd) was 2.68 ± 0.55 L/kg, and the systemic clearance was 4.95 ± 1.20 mL/h/kg. Afoxolaner plasma protein binding was >99.9% in dogs. One major metabolite, formed following hydroxylation of afoxolaner, was identified in dog plasma, urine and bile. When afoxolaner is administered orally, there is a strong correlation between afoxolaner plasma concentration and efficacy with EC90 values of 23 ng/mL for Ctenocephalides felis and ≥ 100 ng/mL for Rhipicephalus sanguineus sensu lato and Dermacentor variabilis. The pharmacokinetic properties of afoxolaner are suited for a monthly administration product because the fast absorption and long terminal half-life support a rapid onset of action while ensuring month-long efficacy. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2017
                23 October 2017
                : 24
                : ( publisher-idID: parasite/2017/01 )
                Affiliations
                [1 ] Clinvet International (Pty) Ltd, PO Box 11186, 9321 Universitas South Africa
                [2 ] Boehringer Ingelheim Animal Health, 29 avenue Tony Garnier, 69007 Lyon France
                Author notes
                [* ]Corresponding author: Frederic.beugnet@ 123456merial.com
                Article
                parasite170101 10.1051/parasite/2017042
                10.1051/parasite/2017042
                5654328
                29063828
                © J. Liebenberg et al., published by EDP Sciences, 2017

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 0, Tables: 4, Equations: 0, References: 19, Pages: 7
                Categories
                Research Article

                aedes aegypti, insecticide, afoxolaner, nexgard®, dog

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