{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:15:01Z","timestamp":1791947701958,"version":"4.3.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T00:00:00Z","timestamp":1565136000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T00:00:00Z","timestamp":1565136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Vet Res"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1186\/s12917-019-2016-4","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T13:03:03Z","timestamp":1565182983000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Suspected neurological toxicity after oral application of fluralaner (Bravecto\u00ae) in a Kooikerhondje dog"],"prefix":"10.1186","volume":"15","author":[{"given":"Daniela","family":"Gaens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Rummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Hamann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2663-1858","authenticated-orcid":false,"given":"Joachim","family":"Geyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,7]]},"reference":[{"issue":"1","key":"2016_CR1","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.bbrc.2009.11.13","volume":"391","author":"Y Ozoe","year":"2010","unstructured":"Ozoe Y, Asahi M, Ozoe F, Nakahira K, Mita T. The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels. Biochem Biophys Res Commun. 2010;391(1):744\u20139. \n                    https:\/\/doi.org\/10.1016\/j.bbrc.2009.11.13\n                    \n                  .","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"2016_CR2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1002\/cmdc.201500516","volume":"11","author":"T Weber","year":"2016","unstructured":"Weber T, Selzer PM. Isoxazolines: a novel Chemotype highly effective on Ectoparasites. Chem Med Chem. 2016;11(3):270\u20136. \n                    https:\/\/doi.org\/10.1002\/cmdc.201500516\n                    \n                  .","journal-title":"Chem Med Chem"},{"issue":"4","key":"2016_CR3","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1021\/tx400055p","volume":"26","author":"P Garcia-Reynaga","year":"2013","unstructured":"Garcia-Reynaga P, Zhao C, Sarpong R, Casida JE. New GABA\/glutamate receptor target for [(3)H]isoxazoline insecticide. Chem Res Toxicol. 2013;26(4):514\u20136. \n                    https:\/\/doi.org\/10.1021\/tx400055p\n                    \n                  .","journal-title":"Chem Res Toxicol"},{"issue":"2","key":"2016_CR4","doi-asserted-by":"publisher","first-page":"154","DOI":"10.3390\/ijerph14020154","volume":"14","author":"S Jiang","year":"2017","unstructured":"Jiang S, Tsikolia M, Bernier UR, Bloomquist JR. Mosquitocidal activity and mode of action of the Isoxazoline Fluralaner. Int J Environ Res Public Health. 2017;14(2):154. \n                    https:\/\/doi.org\/10.3390\/ijerph14020154\n                    \n                  .","journal-title":"Int J Environ Res Public Health"},{"key":"2016_CR5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ibmb.2013.11.009","volume":"45","author":"M Gassel","year":"2014","unstructured":"Gassel M, Wolf C, Noack S, Williams H, Ilg T. The novel isoxazoline ectoparasiticide fluralaner: selective inhibition of arthropod gamma-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal\/acaricidal activity. Insect Biochem Mol Biol. 2014;45:111\u201324 \n                    https:\/\/doi.org\/10.1016\/j.ibmb.2013.11.009\n                    \n                  .","journal-title":"Insect Biochem Mol Biol"},{"key":"2016_CR6","unstructured":"European Medicines Agency. Simparica : EPAR \u2013 Public assessment report, CVMP assessment report for Simparica (EMEA\/V\/C\/003991\/0000). \n                    https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/simparica-epar-public-assessment-report_en.pdf\n                    \n                  . Accessed 13 Mar 2019."},{"key":"2016_CR7","unstructured":"European Medicines Agency. Bravecto: EPAR \u2013 Public assessment report, CVMP assessment report for Bravecto (EMEA\/V\/C\/002526\/0000). \n                    https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/bravecto-epar-public-assessment-report_en.pdf\n                    \n                  . Accessed 13 Mar 2019."},{"key":"2016_CR8","unstructured":"U.S. Food & Drug Administration. Animal drug safety communication: FDA alerts pet owners and veterinarians about potential for neurological adverse events associated with certain flea and tick products. \n                    https:\/\/www.fda.gov\/animal-veterinary\/cvm-updates\/animal-drug-safety-communication-fda-alerts-pet-owners-and-veterinarians-about-potential-neurologic\n                    \n                  . Accessed 4 June 2019."},{"key":"2016_CR9","unstructured":"European Medicines Agency. Tick and flea control agent Bravecto continues to be acceptably safe to use. \n                    https:\/\/www.ema.europa.eu\/en\/news\/tick-flea-control-agent-bravecto-continues-be-acceptably-safe-use\n                    \n                  . Accessed 13 Mar 2019."},{"key":"2016_CR10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/1756-3305-7-83","volume":"7","author":"N Rohdich","year":"2014","unstructured":"Rohdich N, Roepke RK, Zschiesche E. A randomized, blinded, controlled and multi-centered field study comparing the efficacy and safety of Bravecto (fluralaner) against frontline (fipronil) in flea- and tick-infested dogs. Parasit Vectors. 2014;7:83. \n                    https:\/\/doi.org\/10.1186\/1756-3305-7-83\n                    \n                  .","journal-title":"Parasit Vectors"},{"key":"2016_CR11","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/1756-3305-7-85","volume":"7","author":"S Kilp","year":"2014","unstructured":"Kilp S, Ramirez D, Allan MJ, Roepke RK, Nuernberger MC. Pharmacokinetics of fluralaner in dogs following a single oral or intravenous administration. Parasit Vectors. 2014;7:85. \n                    https:\/\/doi.org\/10.1186\/1756-3305-7-85\n                    \n                  .","journal-title":"Parasit Vectors"},{"issue":"5","key":"2016_CR12","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1124\/mol.117.109413","volume":"92","author":"Y Nakata","year":"2017","unstructured":"Nakata Y, Fuse T, Yamato K, Asahi M, Nakahira K, Ozoe F, et al. A single amino acid substitution in the third transmembrane region has opposite impacts on the selectivity of the Parasiticides Fluralaner and Ivermectin for ligand-gated chloride channels. Mol Pharmacol. 2017;92(5):546\u201355 \n                    https:\/\/doi.org\/10.1124\/mol.117.109413\n                    \n                  .","journal-title":"Mol Pharmacol"},{"issue":"6","key":"2016_CR13","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1042\/BST0371404","volume":"37","author":"Ian McGonigle","year":"2009","unstructured":"McGonigle I, Lummis SC. RDL receptors. Biochem Soc Trans 2009;37(Pt 6):1404\u20131406. doi: \n                    https:\/\/doi.org\/10.1042\/BST0371404\n                    \n                  .","journal-title":"Biochemical Society Transactions"},{"issue":"48","key":"2016_CR14","doi-asserted-by":"publisher","first-page":"40232","DOI":"10.1074\/jbc.R112.406280","volume":"287","author":"AJ Wolstenholme","year":"2012","unstructured":"Wolstenholme AJ. Glutamate-gated chloride channels. J Biol Chem. 2012;287(48):40232\u20138. \n                    https:\/\/doi.org\/10.1074\/jbc.R112.406280\n                    \n                  .","journal-title":"J Biol Chem"},{"issue":"5","key":"2016_CR15","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1021\/jf4050809","volume":"62","author":"C Zhao","year":"2014","unstructured":"Zhao C, Casida JE. Insect gamma-aminobutyric acid receptors and isoxazoline insecticides: toxicological profiles relative to the binding sites of [(3)H]fluralaner, [(3)H]-4\u2032-ethynyl-4-n-propylbicycloorthobenzoate, and [(3)H]avermectin. J Agric Food Chem. 2014;62(5):1019\u201324. dx. \n                    https:\/\/doi.org\/10.1021\/jf4050809\n                    \n                  .","journal-title":"J Agric Food Chem"},{"issue":"1\u20132","key":"2016_CR16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.jphysparis.2011.09.012","volume":"106","author":"C Bouzat","year":"2012","unstructured":"Bouzat C. New insights into the structural bases of activation of Cys-loop receptors. J Physiol Paris. 2012;106(1\u20132):23\u201333. \n                    https:\/\/doi.org\/10.1016\/j.jphysparis.2011.09.012\n                    \n                  .","journal-title":"J Physiol Paris"},{"key":"2016_CR17","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/bs.apha.2014.10.002","volume":"72","author":"W Sieghart","year":"2015","unstructured":"Sieghart W. Allosteric modulation of GABAA receptors via multiple drug-binding sites. Adv Pharmacol. 2015;72:53\u201396. \n                    https:\/\/doi.org\/10.1016\/bs.apha.2014.10.002\n                    \n                  .","journal-title":"Adv Pharmacol"},{"issue":"1","key":"2016_CR18","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.tvjl.2010.06.012","volume":"189","author":"I Gramer","year":"2011","unstructured":"Gramer I, Leidolf R, D\u00f6ring B, Klintzsch S, Kr\u00e4mer EM, Yalcin E, et al. Breed distribution of the nt230(del4) MDR1 mutation in dogs. Vet J. 2011;189(1):67\u201371. \n                    https:\/\/doi.org\/10.1016\/j.tvjl.2010.06.012\n                    \n                  .","journal-title":"Vet J"},{"issue":"8","key":"2016_CR19","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1097\/00008571-200111000-00012","volume":"11","author":"KL Mealey","year":"2001","unstructured":"Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001;11(8):727\u201333.","journal-title":"Pharmacogenetics."},{"issue":"6","key":"2016_CR20","doi-asserted-by":"publisher","first-page":"969","DOI":"10.2174\/138920112800399301","volume":"13","author":"J Geyer","year":"2012","unstructured":"Geyer J, Janko C. Treatment of MDR1 mutant dogs with macrocyclic lactones. Curr Pharm Biotechnol. 2012;13(6):969\u201386.","journal-title":"Curr Pharm Biotechnol"},{"key":"2016_CR21","unstructured":"Geyer J, Walther F, Roepke R. Interaction of the isoxazoline drug fluralaner with the multidrug efflux transporter MDR1. In: Proceedings of: Tagung der DVG- Fachgruppe Parasitologie und Parasit\u00e4re Krankheiten: Veterin\u00e4rparasitologie: neue Forschungsergebnisse und aktuelle Probleme in der Praxis. Gie\u00dfen; July 2018. p. 2\u20134."},{"key":"2016_CR22","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1186\/s13071-014-0481-y","volume":"7","author":"FM Walther","year":"2014","unstructured":"Walther FM, Fisara P, Allan MJ, Roepke RK, Nuernberger MC. Safety of concurrent treatment of dogs with fluralaner (Bravecto) and milbemycin oxime-praziquantel. Parasit Vectors. 2014;7:481. \n                    https:\/\/doi.org\/10.1186\/s13071-014-0481-y\n                    \n                  .","journal-title":"Parasit Vectors"},{"issue":"7","key":"2016_CR23","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1023\/A:1006321625243","volume":"23","author":"S Sabnis","year":"1999","unstructured":"Sabnis S. Factors influencing the bioavailability of peroral formulations of drugs for dogs. Vet Res Commun. 1999;23(7):425\u201347.","journal-title":"Vet Res Commun"},{"issue":"7","key":"2016_CR24","doi-asserted-by":"publisher","first-page":"2494","DOI":"10.1002\/jps.21602","volume":"98","author":"K Sagawa","year":"2009","unstructured":"Sagawa K, Li F, Liese R, Sutton SC. Fed and fasted gastric pH and gastric residence time in conscious beagle dogs. J Pharm Sci. 2009;98(7):2494\u2013500. \n                    https:\/\/doi.org\/10.1002\/jps.21602\n                    \n                  .","journal-title":"J Pharm Sci"},{"issue":"1","key":"2016_CR25","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1208\/s12248-008-9011-1","volume":"10","author":"S Fleischer","year":"2008","unstructured":"Fleischer S, Sharkey M, Mealey K, Ostrander EA, Martinez M. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AAPS J. 2008;10(1):110\u20139. \n                    https:\/\/doi.org\/10.1208\/s12248-008-9011-1\n                    \n                  .","journal-title":"AAPS J"},{"key":"2016_CR26","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1146\/annurev.nu.16.070196.002123","volume":"16","author":"PG Welling","year":"1996","unstructured":"Welling PG. Effects of food on drug absorption. Annu Rev Nutr. 1996;16:383\u2013415.","journal-title":"Annu Rev Nutr"},{"issue":"10","key":"2016_CR27","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.2165\/00003495-200262100-00005","volume":"62","author":"LE Schmidt","year":"2002","unstructured":"Schmidt LE, Dalhoff K. Food-drug interactions. Drugs. 2002;62(10):1481\u2013502.","journal-title":"Drugs."},{"key":"2016_CR28","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/1756-3305-7-84","volume":"7","author":"FM Walther","year":"2014","unstructured":"Walther FM, Allan MJ, Roepke RK, Nuernberger MC. The effect of food on the pharmacokinetics of oral fluralaner in dogs. Parasit Vectors. 2014;7:84. \n                    https:\/\/doi.org\/10.1186\/1756-3305-7-84\n                    \n                  .","journal-title":"Parasit Vectors"},{"issue":"3","key":"2016_CR29","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/0163-7258(95)02043-8","volume":"69","author":"GA Johnston","year":"1996","unstructured":"Johnston GA. GABAA receptor pharmacology. Pharmacol Ther. 1996;69(3):173\u201398.","journal-title":"Pharmacol Ther"},{"key":"2016_CR30","first-page":"313","volume":"57","author":"S Held","year":"2012","unstructured":"Held S, Gramer I, Ha\u00dfdenteufel E, Neiger R, Geyer J. Therapie einer Avermectin-Intoxikation bei zwei Hunden mit homozygotem nt230(del4)-MDR1-Gendefekt durch Lipidinfusion. Kleintierpraxis. 2012;57:313\u20139.","journal-title":"Kleintierpraxis."}],"container-title":["BMC Veterinary Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12917-019-2016-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12917-019-2016-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12917-019-2016-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T23:23:47Z","timestamp":1596669827000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcvetres.biomedcentral.com\/articles\/10.1186\/s12917-019-2016-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,7]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["2016"],"URL":"https:\/\/doi.org\/10.1186\/s12917-019-2016-4","relation":{},"ISSN":["1746-6148"],"issn-type":[{"value":"1746-6148","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,7]]},"assertion":[{"value":"18 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent was obtained from the owner of the dog for publication of this case report and the accompanying video.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The author\u2019s declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"283"}}