GABAergic Neurotransmission and Toxicity 3: Isoxazolines

Abstract

The isoxazolines are a series of antiparasitic substances containing a modified isoxazoline ring system. They are typified by fluralaner, afoxolaner, sarolaner and lotilaner and are most often formulated as chewable tablets for the control of fleas and ticks on companion animals. Fluralaner is also authorised in some jurisdictions for the treatment of mites on chickens. These substances are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and are non-competitive GABA receptor antagonists, which activate electrophysiological disruption of the nervous systems in parasites, ultimately resulting in death. The available data suggest that these drugs have excellent safety profiles in veterinary patients, even at multiples of the recommended therapeutic doses. The results of conventional toxicity tests are lacking, but the data from regulatory sources indicate a low order of toxicity. Pharmacovigilance data suggest that neurotoxicity, particularly ataxia and convulsions in dogs, may be related to exposure to these substances. However, it is not clear if a GABA target is involved or, indeed, if the background frequency of convulsions is higher than or comparable to the background frequency in the canine population.