Isoxazolines are pesticides of a new chemical class introduced in the 2010s. They have been launched first (2013) as veterinary products against fleas and ticks in dogs, but are also effective against numerous other external veterinary and agricultural parasites.
They can be considered as classic synthetic pesticides both by their mode of action and by their general features. They are not naturally produced molecules, but are manufactured following usual industrial chemical processes.
Isoxazolines are all derivatives of isoxazole.
They have a broad spectrum of insecticidal and acaricidal activity and are effective against a number of veterinary parasites such as fleas and ticks. In laboratory studies they have also shown efficacy against houseflies, mosquitoes and blowfly larvae. So far they have been introduced mainly for use in dogs. Most available products (NEXGARD, NEXGARD SPECTRA, BRAVECTO, SIMPARICA) are for oral administration to dogs, BRAVECTO topical solution is a topical spot-on for dogs and cats.
Other isoxazolines have shown anti-microbial and anti-cancer efficacy.
Several agrochemical and pharmaceutical companies (e.g. DU PONT, BAYER, BASF, MSD ANIMAL HEALTH, NOVARTIS AH, SYNGENTA, etc.) have filed patents on various types of isoxazoline derivatives in the last years. New veterinary antiparasitics of this chemical class are likely to appear in the future. However, it seems that they are unsuitable for use in crops under field conditions and they may be used only as Animal Health products.
Click here for a general introduction to ectoparasiticides and their most important features.
Mode of action and characteristics of isoxazolines
Isoxazolines with insecticidal and tickicidal efficacy are non-competitive GABA (gamma-aminobutyric acid) receptor antagonists, much more selective for GABA receptors in insects or ticks, than for those in mammals, including humans. They bind to chloride channels in nerve and muscle cells, which blocks the transmission of neuronal signals. Affected parasites are paralyzed and die.
Isoxazolines approved for veterinary use have a systemic mode of action. Ingested or topically administered, isoxazolines are rapidly absorbed into blood and distributed throughout the whole body of the host. Blood-sucking parasites (mainly fleas and ticks) are killed during their blood meal.
But the systemic mode of action means also that for fleas and/or ticks to be killed, they have to bite the dog first and suck enough blood before the ingested active ingredient kills them. Whether killing is fast enough to prevent disease transmission is not yet known.
The isoxazolines approved for veterinary use so far are the following:
- Afoxolaner: used in dogs against fleas, and some ticks species (NEXGARD and NEXGARD SPECTRA from MERIAL).
- Fluralaner: used in dogs and cats against fleas, and some ticks species (BRAVECTO oral chews and BRAVECTO topical solution from MERCK ANIMAL HEALTH).
- Sarolaner: approved as an oral tablet for dogs against fleas, & ticks,and certain mites (SIMPARICA from ZOETIS).
- Lotilaner: patented by NOVARTIS AH (now ELANCO). Registration requested in Australia in 2016 for chewable tablets for dogs (CREDELIO).
Interestingly, both afoxolaner and fluralaner have been described first by DU PONT DE NEMOURS and NISSAN, respectively, but have been introduced as veterinary parasiticides by other companies (afoxolaner by MERIAL, fluralaner by MERCK ANIMAL HEALTH). This is rather unusual, since most active ingredients used in veterinary ectoparasiticides were first introduced for crop protection and only afterwards for use on animals, ivermectin being one of the very few notorious exceptions. Sarolaner has been both discovered and developed by ZOETIS.
Safety of isoxazolines
Published information on safety and toxicity of isoxazolines is still very scarce.
Target Animal Safety studies done on products approved for dogs indicate that such products are well tolerated by dogs at the therapeutic dose. Beagle dogs treated at up to 5 times the therapeutic dose with approved products showed no signs of intoxication.
Due to their recent introduction there is very little knowledge on tolerance in different dog or cat breeds or in young, old or otherwise weak animals.
Additional specific information (toxicity, intoxication symptoms, adverse drug reactions, antidote, etc.) on the safety of isoxazoline active ingredients for veterinary use is available in specific articles in this site:
General information on the safety of veterinary antiparasitics is available in specific articles in this site (click to visit):
- General safety of antiparasitics for domestic animals
- General safety of antiparasitics for humans
- General safety of antiparasitics for the environment