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      The speed of kill of fluralaner (Bravecto™) against Ixodes ricinus ticks on dogs

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          Abstract

          Background

          Pathogens that are transmitted by ticks to dogs, such as Anaplasma phagocytophilum, Babesia spp., Borrelia burgdorferi sensu latu, and Ehrlichia canis, are an increasing problem in the world. One method to prevent pathogen transmission to dogs is to kill the ticks before transmission occurs. Fluralaner (Bravecto™) is a novel isoxazoline insecticide and acaricide that provides long persistent antiparasitic activity following systemic administration. This study investigated the speed of kill of fluralaner against Ixodes ricinus ticks on dogs.

          Methods

          A total of 48 dogs were randomized to 8 groups of 6 dogs and each dog was infested with 50 female and 10 male I. ricinus ticks. Two days later (day 0), 4 groups received a single treatment of 25 mg fluralaner/kg body weight as Bravecto™ chewable tablets; the dogs in the other 4 groups were left untreated. Separate control and treatment groups were paired at each time point (4, 8, 12, or 24 hours after treatment) for assessment of tick-killing efficacy. At 4, 8, and 12 weeks after treatment, all dogs were re-infested with 50 female I. ricinus ticks and subsequently assessed for live or dead ticks at either 4, 8, 12, or 24 hours after re-infestation. Efficacy was calculated for each assessment time point by comparison of the treatment group with the respective control group.

          Results

          Tick-killing efficacy was 89.6% at 4 hours, 97.9% at 8 hours, and 100% at 12 and 24 hours after treatment. Eight hours after re-infestation, efficacy was 96.8%, 83.5%, and 45.8% at 4, 8, and 12 weeks after treatment, respectively. At least 98.1% tick-killing efficacy was demonstrated 12 and 24 hours after re-infestation over the entire 12 week study period.

          Conclusions

          Fluralaner kills ticks rapidly after treatment at 4 hours, and over its entire 12-week period of efficacy, it achieves an almost complete killing effect within 12 hours after tick infestation. The rapid tick-killing effect together with the long duration of efficacy enables fluralaner to aid in the prevention of tick borne diseases.

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          Most cited references35

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          Lyme borreliosis.

          Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            The novel isoxazoline ectoparasiticide fluralaner: selective inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/acaricidal activity.

            Isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and L-glutamate-gated chloride channels (GluCls). In this study, the effects of the isoxazoline drug fluralaner on insect and acarid GABACl (RDL) and GluCl and its parasiticidal potency were investigated. We report the identification and cDNA cloning of Rhipicephalus (R.) microplus RDL and GluCl genes, and their functional expression in Xenopus laevis oocytes. The generation of six clonal HEK293 cell lines expressing Rhipicephalus microplus RDL and GluCl, Ctenocephalides felis RDL-A285 and RDL-S285, as well as Drosophila melanogaster RDLCl-A302 and RDL-S302, combined with the development of a membrane potential fluorescence dye assay allowed the comparison of ion channel inhibition by fluralaner with that of established insecticides addressing RDL and GluCl as targets. In these assays fluralaner was several orders of magnitude more potent than picrotoxinin and dieldrin, and performed 5-236 fold better than fipronil on the arthropod RDLs, while a rat GABACl remained unaffected. Comparative studies showed that R. microplus RDL is 52-fold more sensitive than R. microplus GluCl to fluralaner inhibition, confirming that the GABA-gated chloride channel is the primary target of this new parasiticide. In agreement with the superior RDL on-target activity, fluralaner outperformed dieldrin and fipronil in insecticidal screens on cat fleas (Ctenocephalides felis), yellow fever mosquito larvae (Aedes aegypti) and sheep blowfly larvae (Lucilia cuprina), as well as in acaricidal screens on cattle tick (R. microplus) adult females, brown dog tick (Rhipicephalus sanguineus) adult females and Ornithodoros moubata nymphs. These findings highlight the potential of fluralaner as a novel ectoparasiticide. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

              A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels. Copyright 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                christina.wengenmayer@msd.de
                heike.williams@msd.de
                eva.zschiesche@msd.de
                andreas.moritz@vetmed.uni-giessen.de
                judith.langenstein@googlemail.com
                rainer.roepke@msd.de
                anja.heckeroth@msd.de
                Journal
                Parasit Vectors
                Parasit Vectors
                Parasites & Vectors
                BioMed Central (London )
                1756-3305
                18 November 2014
                18 November 2014
                2014
                : 7
                : 1
                : 525
                Affiliations
                [ ]MSD Animal Health Innovation GmbH, Zur Propstei, 55270 Schwabenheim, Germany
                [ ]Department of Veterinary Clinical Sciences, Clinical Pathophysiology and Clinical Pathology, Justus-Liebig-University Giessen, Giessen, Germany
                Article
                525
                10.1186/s13071-014-0525-3
                4247686
                25406442
                c7105ee4-727b-4506-b006-bc1e7508c4e8
                © Wengenmayer et al.; licensee BioMed Central Ltd. 2014

                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 credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 25 July 2014
                : 5 November 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Parasitology
                bravecto™ chewable tablets,fluralaner,speed of kill,dog,tick,ixodes ricinus,tick-borne diseases,efficacy

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