Mosquitocidal Activity and Mode of Action of the Isoxazoline Fluralaner

Abstract

Mosquitoes, such as Aedes aegypti and Anopheles gambiae, are important vectors of human diseases. Fluralaner, a recently introduced parasiticide, was evaluated as a mosquitocide in this study. On Ae. aegypti and An. gambiae fourth-instar larvae, fluralaner had 24-h LC50 (lethal concentration for 50% mortality) values of 1.8 ppb and 0.4 ppb, respectively. Following topical application to adult Ae. aegypti, fluralaner toxicity reached a plateau in about 3 days, with 1- and 3-day LD50 (lethal dose for 50% mortality) values of 1.3 ng/mg and 0.26 ng/mg, suggesting a slowly developing toxicity. Fipronil outperformed fluralaner by up to 100-fold in adult topical, glass contact, and feeding assays on Ae. aegypti. These data show that fluralaner does not have exceptional toxicity to mosquitoes in typical exposure paradigms. In electrophysiological recordings on Drosophila melanogaster larval central nervous system, the effectiveness of fluralaner for restoring nerve firing after gamma-aminobutyric acid (GABA) treatment, a measure of GABA antagonism, was similar in susceptible Oregon-R and cyclodiene-resistant rdl-1675 strains, with EC50 (half maximal effective concentration) values of 0.34 µM and 0.29 µM. Although this finding suggests low cross resistance in the presence of rdl, the moderate potency, low contact activity, and slow action of fluralaner argue against its use as an adult mosquitocide for vector control.

Characterizing Permethrin and Etofenprox Resistance in Two Common Laboratory Strains of Anopheles gambiae (Diptera: Culicidae)

“…The caveat to this first-instar bioassay was that these small larvae were more susceptible to xenobiotics and may not provide an accurate prediction of mortality for later instars or adults. This effect was recently highlighted by comparing the toxicity of fluralaner to Aedes aegypti mosquito larvae [23]. Fluralaner’s toxicity to Ae.…”

“…Fluralaner’s toxicity to Ae. aegypti fourth-instar larvae was found to be 1.8 ppb [23]; however, a previous study reported greater than 90% mortality to first instar Ae. Aegypti larvae at 1.2 ppt [24], a greater than 1500-fold difference in toxicity between the two life stages.…”

Synthesis and structure–activity relationships of carbohydrazides and 1,3,4‐oxadiazole derivatives bearing an imidazolidine moiety against the yellow fever and dengue vector, Aedes aegypti

“…Electrophysiological recordings from the larval central nervous system (CNS) were performed essentially as previously described. 25 The CNS was dissected in physiological saline containing (M) NaCl (0.157), KCl (0.003), CaCl 2 (0.002) and HEPES (0.004), at pH 7.2, and transected posterior to the cerebral lobes to eliminate the blood–brain barrier and facilitate penetration of chemicals into the CNS. A recording glass pipette suction electrode was used to monitor descending spike activity from several peripheral nerve trunks.…”

Suspected neurological toxicity after oral application of fluralaner (Bravecto®) in a Kooikerhondje dog

“…Isoxazolines are potent inhibitors of gamma-aminobutyric acid (GABA)- and glutamate-gated chloride channels in the nervous system of invertebrates [3]. Thereby, they result in uncontrolled neural activity and finally death of insects and acarines [4]. Binding to and blocking of phylogenetically related vertebrate pentameric ligand-gated chloride channels (i.e.…”