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      Efficacy of oral afoxolaner for the treatment of canine generalised demodicosis Translated title: Efficacité de l’afoxolaner par voie orale pour le traitement de la démodécie canine généralisée

      1 , * , 1 , 1 , 2

      Parasite

      EDP Sciences

      Demodex canis, Demodicosis, Treatment, Afoxolaner, NexGard®, Dog

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          Abstract

          The efficacy of oral treatment with a chewable tablet containing afoxolaner 2.27% w/w (NexGard ®, Merial) administered orally was assessed in eight dogs diagnosed with generalised demodicosis and compared with efficacy in eight dogs under treatment with a topical combination of imidacloprid/moxidectin (Advocate ®, Bayer). Afoxolaner was administered at the recommended dose (at least 2.5 mg/kg) on Days 0, 14, 28 and 56. The topical combination of imidacloprid/moxidectin was given at the same intervals at the recommended concentration. Clinical examinations and deep skin scrapings were performed every month in order to evaluate the effect on mite numbers and the resolution of clinical signs. The percentage reductions of mite counts were 99.2%, 99.9% and 100% on Days 28, 56 and 84, respectively, in the afoxolaner-treated group, compared to 89.8%, 85.2% and 86.6% on Days 28, 56 and 84 in the imidacloprid/moxidectin-treated group. Skin condition of the dogs also improved significantly from Day 28 to Day 84 in the afoxolaner-treated group. Mite reductions were significantly higher on Days 28, 56 and 84 in the afoxolaner-treated group compared to the imidacloprid/moxidectin-treated group. The results of this study demonstrated that afoxolaner, given orally, was effective in treating dogs with generalised demodicosis within a two-month period.

          Translated abstract

          L’efficacité d’un traitement par comprimés appétents contenant de l’afoxolaner 2.27 % w/w (NexGard ®, Merial), administré oralement, a été évaluée chez 8 chiens atteints de démodécie généralisée, et comparée avec l’efficacité chez 8 chiens d’une application topique de la combinaison imidaclopride/moxidectine (Advocate ®, Bayer). L’afoxolaner était administré à la dose recommandée (au minimum 2.5 mg/kg) aux jours 0, 14, 28 et 56. La combinaison imidaclopride/moxidectine était administrée aux mêmes intervalles à la dose recommandée. Les examens cliniques et les raclages cutanés profonds ont été réalisés chaque mois pour évaluer la réduction du nombre d’acariens et la résolution des signes cliniques. Les pourcentages de réduction du nombre d’acariens ont été de 99.2 %, 99.9 % et 100 % aux jours 28, 56, et 84, respectivement, dans le groupe traité avec l’afoxolaner, comparé à 89.8 %, 85.2 %, et 86.6 % aux jours 28, 56, et 84 pour le groupe traité avec imidaclopride/moxidectine. Les signes dermatologiques se sont considérablement améliorés du jour 28 au jour 84 dans le groupe traité avec l’afoxolaner. La réduction du nombre d’acariens a été significativement plus importante aux jours 28, 56, et 84 dans le groupe traité avec l’afoxolaner par rapport au groupe traité avec imidaclopride/moxidectine. Les résultats de cette étude démontrent que l’afoxolaner, administré oralement, est efficace dans le traitement de la démodécie généralisée chez le chien dans une période de deux mois.

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          Most cited references 21

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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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            Efficacy of orally administered fluralaner (BravectoTM) or topically applied imidacloprid/moxidectin (Advocate®) against generalized demodicosis in dogs

            Background This laboratory study compared the efficacy of Bravecto™ (fluralaner), formulated as a chewable tablet, with the efficacy of Advocate® (imidacloprid/moxidectin), formulated for topical administration, against naturally acquired generalized demodicosis in dogs. Methods Sixteen dogs, all diagnosed with generalized demodectic mange, were randomly allocated to two equal groups. Bravecto™ chewable tablets were administered once orally at a minimum dose of 25 mg fluralaner/kg body weight to one group of dogs, while the second group was treated topically on three occasions at 28-day intervals with Advocate® at a minimum dose of 10 mg imidacloprid/kg body weight and 2.5 mg moxidectin/kg body weight. Mites were counted in skin scrapings and demodectic lesions were evaluated on each dog before treatment and at 28-day intervals thereafter over a 12 week study period. Deep skin scrapings (~4 cm2) were made from the same five sites on each dog at each subsequent examination. Results After single oral administration of Bravecto™ chewable tablets, mite numbers in skin scrapings were reduced by 99.8% on Day 28 and by 100% on Days 56 and 84. Mite numbers in the dogs treated topically on three occasions at 28-day intervals with Advocate® were reduced by 98.0% on Day 28, by 96.5% on Day 56 and by 94.7% on Day 84. Statistically significantly (P ≤ 0.05) fewer mites were found on Days 56 and 84 on the Bravecto™ treated dogs compared to Advocate® treated dogs. A marked decrease was observed in the occurrence of erythematous patches, crusts, casts and scales in the dogs treated with Bravecto™ and in the occurrence of erythematous patches in the dogs treated with Advocate®. With the exception of one dog in each treated group, all dogs exhibited hair regrowth ≥ 90% at the end of the study in comparison with their hair-coat at study start. Conclusions Single oral administration of Bravecto™ chewable tablets is highly effective against generalized demodicosis, with no mites detectable at 56 and 84 days following treatment. In comparison, Advocate®, administered three times at 28-day intervals, is also highly effective against generalized demodicosis, but most dogs still harboured mites at all assessment time points. Both treatments resulted in a marked reduction of skin lesions and increase of hair re-growth 12 weeks after the initial treatment.
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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
                2016
                24 March 2016
                : 23
                : ( publisher-idID: parasite/2016/01 )
                Affiliations
                [1 ] Merial S.A.S. 29 avenue Tony Garnier 69007 Lyon France
                [2 ] Clinvet International (Pty) Ltd PO Box 11186 9321 Universitas South Africa
                Author notes
                [* ]Corresponding author: frederic.beugnet@ 123456merial.com
                Article
                parasite160008 10.1051/parasite/2016014
                10.1051/parasite/2016014
                4807374
                27012161
                © F. Beugnet et al., published by EDP Sciences, 2016

                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: 6, Equations: 2, References: 29, Pages: 8
                Categories
                Research Article

                nexgard®, afoxolaner, treatment, demodicosis, demodex canis, dog

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