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Antiparasitics in Animal Health: Quo Vadis?

2020; Elsevier BV; Volume: 37; Issue: 1 Linguagem: Inglês

10.1016/j.pt.2020.09.004

1471-5007

Paul M. Selzer, Christian Epe,

Bird parasitology and diseases

Antiparasitics for the treatment of companion animals and livestock is one of the largest global market segments in the animal health industry.Parasitic infections caused by endo- and ectoparasites – the latter also transmitting vector-borne diseases – are among the most significant diseases worldwide, in both animals and humans.Most of the antiparasitic active pharmaceutical ingredients were developed more than 20 years ago. Isoxazolines, which first entered the market in 2014, are one of the very rare exceptions and a true success story. Currently, the four leading animal health companies market four isoxazolines in diverse dog and cat products.Drug and multidrug resistance is increasingly common across all parasites. In livestock, it is a significant and widespread problem. In dogs and cats, drug resistance is as yet less serious.The discovery of novel antiparasitics is of utmost importance to overcome resistance and to fill the development pipeline. Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. Antiparasitics acting on endo- or ectoparasites represent the second largest segment of the global animal health market, accounting for 23% of market share. However, relatively few novel antiparasitic agents have been introduced into the market during recent decades. One exception, and a groundbreaking 21st century success story, are the isoxazolines, whose full potential has not yet been entirely explored. Unfortunately, resistance issues are present across most parasitic diseases, which generates a clear market need for novel resistance-breaking antiparasitics with new modes/mechanisms of action. Recent advances in science and technologies strongly suggest that the time is right to invest in new modalities such as parasitic vaccines or in environmentally friendly interventions. Animal health is focused on the management and control of diseases in order to ensure the health of both livestock (see Glossary) and companion animals. The global market for animal health products approaches €30 billion per year, with an annual growth rate outstripping that of human medicine. Products include biologicals (e.g., vaccines), antiparasitics/parasiticides, anti-infectives (e.g., antibiotics, antifungals), other pharmaceuticals (e.g., antihypertensives, antidiabetics), and medical feed additives (Figure 1, Key Figure). The current animal health market is understood to be driven primarily by three factors:(i)Pet owners, farmers, and veterinarians prefer more technically advanced and more convenient treatments.(ii)The growing world population increasingly demands affordable sources of protein from food animals and animal products, requiring improvements in livestock health care.(iii)The development of resistance requires new resistance-breaking preventatives and treatments. Due to the high economic impact and the immediate relevance for animal health, antiparasitics, also referred to as parasiticides, currently represent the second largest segment of the global animal health market – taking turns almost on a yearly basis with biologicals as the largest segment – accounting for €7 billion in sales (23% of the market share) (Figure 1, Figure 2). In addition, animal health plays an important role in furthering the 'One Health' initiative, which is dedicated to improving the lives of all species – human and animal – through the integration of human medicine, veterinary medicine, and environmental sciencei. Parasitic infections account for some of the most significant diseases worldwide, in both animals and humans, and are of enormous socioeconomic importance. Despite significant treatment advances in the preceding half century, they remain a major threat to livestock farming and cause large deficits for the agricultural economy. Effective parasite control is thus essential for profitability in intensive livestock production [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Parasites also affect the well-being of companion animals and, due to their often zoonotic nature, represent threats to human health. Infections of humans with parasitic helminths belong to the most frequent infectious diseases worldwide, estimated to affect up to 25% of the world population, especially in warmer climates. Prevention of parasite infections in animals is not only necessary for animal welfare, and the human–animal bond, but it also reduces the risk of transmission to humans [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Parasites are generally classified as endo- or ectoparasites, depending on whether they live in or on the host, respectively. Ectoparasites, such as fleas, ticks, lice, or flies are, with some exceptions (e.g., Cochlyomyia-induced myiasis in South America or tick paralysis in Australia), not life-threatening by themselves but can reduce food intake, produce toxins, and/or cause traumatic damage due to lesions, leading to a significant impairment of well-being and performance, such as weight gain or milk production. In addition, the major threat related to ectoparasites is that many of them (e.g., ticks) are effective vectors for the transmission of severe diseases [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Most active pharmaceutical ingredients (APIs) for ectoparasitics originated from research/discovery in crop protection, and many of the leading animal health companies in the ectoparasiticides sector have existing or historical links to crop protection businesses [3.Sparks T.C. Insecticide discovery: an evaluation and analysis.Pestic. Biochem. Physiol. 2013; 107: 8-17Crossref PubMed Scopus (143) Google Scholar,4.Sparks T.C. et al.The new age of insecticide discovery-the crop protection industry and the impact of natural products.Pestic. Biochem. Physiol. 2019; 161: 12-22Crossref PubMed Scopus (46) Google Scholar]. Endoparasites, such as parasitic worms and protozoa, cause both subclinical diseases as well as clinical manifestations with high morbidity and mortality. Despite their medical and socioeconomic importance, current treatments and prevention still rely primarily on old chemotherapeutic or chemo-metaphylactic control programs [1.Deplazes P. et al.Parasitology in Veterinary Medicine. Wageningen Academic Publishers, 2016Crossref Google Scholar,2.Mehlhorn H. Encyclopedia of Parasitology.4th edn. Springer Nature, 2016Google Scholar]. Only a very few drugs with antiparasitic activity have been introduced to the market in recent years; these include the sheep anthelmintic APIs monepantel (Zolvix®) [5.Kaminsky R. et al.A new class of anthelmintics effective against drug-resistant nematodes.Nature. 2008; 452: 176-180Crossref PubMed Scopus (367) Google Scholar] and derquantel (Startect®, a combination of derquantel and abamectin) [6.Geurden T. et al.The efficacy of a combined oral formulation of derquantel-abamectin against anthelmintic resistant gastro-intestinal nematodes of sheep in the UK.Vet. Parasitol. 2012; 189: 308-316Crossref PubMed Scopus (13) Google Scholar], and the chemical class of isoxazolines as ectoparasiticides for dogs and cats [7.Weber T. Selzer P.M. Isoxazolines: a novel chemotype highly effective on ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref PubMed Scopus (58) Google Scholar]. Most of the antiparasitic APIs widely used today were developed more than 20 years ago, and the market is driven to a large extent by generics and drugs offering similar profiles [8.Geary T.G. et al.Target identification and mechanism-based screening for anthelmintics: application of veterinary antiparasitic research programs to search for new antiparasitic drugs for human indications.in: Selzer P.M. Antiparasitic and Antibacterial Drug Discovery. Wiley-VCH, 2009: 3-15Crossref Scopus (25) Google Scholar]. Animal health companies have focused largely on incremental innovations that meet, and modestly surpass, existing customers' expectations. Accordingly, the market environment is highly competitive. More than 70% of the market share is held by four major market players in animal health: Zoetis, Boehringer Ingelheim Animal Health, MSD Animal Health, and Elanco/Bayer Animal Health. Antiparasitic innovation is notably driven by the same four companies that have access to the vast majority of antiparasitic research (Figure 2). Nevertheless, the antiparasitic market remains extremely attractive and is, for an animal health business, a key market due to the high market volume and global relevance. An entry into this field requires a thorough evaluation of possible options, the development of an integrated strategic concept, and an organizational commitment to work towards this goalii. A substantial number of active ingredients have been developed into products for the treatment and control of animal parasites. The traditional differentiation of endo- and ectoparasiticides has become blurred with the advent, in the 1980s, of chemical compounds (e.g., avermectins/milbemycins) that provide activity against both categories. The capacity to control both endo- and ectoparasites has led to the definition of endectocides. Endectocides can be based on specific molecules and dosages, or on specific combinations. Resistance issues on the one hand – in distinct geographic regions and parasite classes – and the search for broad-spectrum activity on the other hand have led increasingly to the development of products that combine two or more active ingredients from the endo- and ectoparasiticide groupings in recent years (Figure 1) [9.Woods D.J. et al.Comparison of anti-ectoparasite and anti-endoparasite therapies and control strategies.in: Meng C.Q. Sluder A.E. Ectoparasites. Wiley-VCH, 2018: 1-23Crossref Scopus (1) Google Scholar]. For companion animals, current products for the treatment of ectoparasites provide efficacy against ticks and fleas with a protection period of at least 1 month. Endoparasiticides, like the macrocyclic lactones, target the major gastrointestinal nematodes and the dog heartworm, Dirofilaria immitis, in endemic areas, while tapeworms are treated via the addition of praziquantel, almost the only cestodicidal drug used in companion animalsiii. Requirements for cattle and small-ruminant products are complex. The major ectoparasitic target has traditionally been prevention and control of ticks and also, in some geographic areas, flies; however, lice are becoming more important. Antiparasitic products should provide protection for a long period to reduce handling of animals. Endoparasiticides, such as the macrocyclic lactones, should control all major gastrointestinal nematodes. Flukes and cestodes are currently controlled by other actives: triclabendazole, closantel, and clorsulon for flukes, praziquantel and niclosamide for cestodesiii. The main classes of antiparasitics are well described in numerous publicationsiii. Endoparasiticides widely in use today comprise benzimidazoles (e.g., fenbendazol), imidazothiazoles (i.e., levamisole), tetrahydropyrimidines (e.g., pyrantel), and macrocyclic lactones (e.g., ivermevctin), which include the avermectins and milbemycins, natural or synthetic derivatives of fermentation products from soil microorganisms (Streptomyces spp). Macrocyclic lactone formulations can have activity against both nematodes and arthropods, and can therefore be used as endectoparasiticides. The ectoparasiticides comprise pyrethrins and synthetic pyrethroids, organophosphates, carbamates, macrocyclic lactones, formamidines, pyrazoles, neonicotinoids, spinosyns, semicarbazones, isoxazolines, and insect growth regulators such as the juvenile hormone analogue S-methoprene and the benzoylphenyl urea lufenuroniii [9.Woods D.J. et al.Comparison of anti-ectoparasite and anti-endoparasite therapies and control strategies.in: Meng C.Q. Sluder A.E. Ectoparasites. Wiley-VCH, 2018: 1-23Crossref Scopus (1) Google Scholar]. The latest class, introduced into the animal health market in 2014, are the isoxazolines (Figure 3) [7.Weber T. Selzer P.M. Isoxazolines: a novel chemotype highly effective on ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref PubMed Scopus (58) Google Scholar]. Although first identified in the agrochemical sector, the isoxazolines represent the largest and probably the most exciting new class of insecticidal and acaricidal molecules introduced for animal health in the 21st century to date (Box 1) [10.Long A. Isoxazolines: preeminent ectoparasiticides of the early twenty-first century.in: Meng C.Q. Sluder A. Ectoparasites. Wiley-VCH, 2018: 319-351Crossref Scopus (4) Google Scholar]. Isoxazolines inhibit γ-aminobutyric acid chloride channels and glutamate-gated chloride channels of insects and acarids (i.e., ticks and mites), making them highly effective ectoparasiticides [7.Weber T. Selzer P.M. Isoxazolines: a novel chemotype highly effective on ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref PubMed Scopus (58) Google Scholar]. To date, the four marketed isoxazoline products include Nexgard® (afoxolaner, from Boehringer Ingelheim AH) [11.Shoop W.L. et al.Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.Vet. Parasitol. 2014; 201: 179-189Crossref PubMed Scopus (122) Google Scholar, 12.Xu M. et al.The discovery of afoxolaner: a new ectoparasiticide for dogs.in: Meng C.Q. Sluder A.E. Ectoparasites: Drug Discovery Against Moving Targets. Wiley-VCH, 2018: 259-271Crossref Scopus (3) Google Scholar, 13.Letendre L. et al.Development of afoxolaner as a new ectoparasiticide for dogs.in: Meng C.Q. Sluder A.E. Ectoparasites. Wiley-VCH, 2018: 273-294Crossref Scopus (3) Google Scholar], Bravecto® (fluralaner, from MSD AH) [14.Gassel M. et al.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: 111-124Crossref PubMed Scopus (160) Google Scholar], Simparica® (sarolaner, from Zoetis) [15.McTier T.L. et al.Discovery of sarolaner: a novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.Vet. Parasitol. 2016; 222: 3-11Crossref PubMed Scopus (85) Google Scholar,16.Woods D.J. McTier T.L. Discovery, development, and commercialization of sarolaner (Simparica®), a novel oral isoxazoline ectoparasiticide for dogs.in: Meng C.Q. Sluder A.E. Ectoparasites. Wiley-VCH, 2018: 295-318Crossref Scopus (3) Google Scholar], and Credelio® (lotilaner, from Elanco) (Figure 3) [17.Rufener L. et al.The novel isoxazoline ectoparasiticide lotilaner (CredelioTM): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls).Parasit. Vectors. 2017; 10: 530Crossref PubMed Scopus (24) Google Scholar].Box 1Industry Consolidation and the Race for InnovationThe development of the isoxazolines showcases the remarkable results of an agrochemical/animal health discovery race combined with a constantly evolving pharmaceutical industry.Nissan patented the first isoxazoline in 2005 [32.Mita, T. et al. Nissan Chemical Industries, Ltd., Japan, (2005). Isoxazoline‐substituted benzamide compound and noxious organism control agent. WO2005085216.Google Scholar]. At that time, Intervet (➔ SP-Intervet and today MSD AH) joined forces with Nissan to discover the ectoparasiticide potential and molecular mode of action of what is known today as fluralaner [33.Heckeroth, A.R. et al. Intervet Int. BV, (2009). Isoxazoline compositions and their use as antiparasitics. WO2009024541.Google Scholar]. DuPont followed with patents on afoxolaner in 2009, which was subsequently developed by Merial (now Boehringer Ingelheim AH) [34.Lahm, G.P. et al. E. I. du Pont de Nemours and Company, (2009). Naphthalene isoxazoline invertebrate pest control agents. WO2009002809.Google Scholar]. Inspired by these activities, Pfizer (today Zoetis, and independent of Pfizer) initiated their internal isoxazoline program in 2009, synthesizing and developing sarolaner [35.Billen, D. et al., Zoetis LLC, (2012). Spirocyclic isoxazoline derivatives as antiparasitic agents. WO2012120399.Google Scholar]. Ely Lilly's Animal Health business, Elanco (today independent of Ely Lilly), last to enter the scene, collaborated with the medicinal chemical company Anacor (later acquired by Pfizer) for the synthesis of respective isoxazolines. Although Anacor successfully delivered on the goal, Elanco developed lotilaner, patented first by Novartis AH and acquired as a result of the takeover of Novartis Animal Health in 2015 [36.Nanchen, S. et al. Novartis AG, (2010). Isoxazoline derivatives and their use as pesticide. WO2010070068.Google Scholar]. Bayer AH followed with an as-yet unmarketed isoxazoline (international nonproprietary name – INN – tigolaner, received in 2017ix, which originated from Bayer Crop Science [37.Maue, M. et al. Bayer Cropscience Aktiengesellschaft, (2014). Halogen-substituted pyrazole derivatives as pest-control agents. WO2014122083Google Scholar].Elanco finalized the acquisition of Bayer AH in August 2020 as a consequence of the takeover of Monsanto by Bayer Crop Sciencevii,viii (see Figure 2 in main text). The development of the isoxazolines showcases the remarkable results of an agrochemical/animal health discovery race combined with a constantly evolving pharmaceutical industry. Nissan patented the first isoxazoline in 2005 [32.Mita, T. et al. Nissan Chemical Industries, Ltd., Japan, (2005). Isoxazoline‐substituted benzamide compound and noxious organism control agent. WO2005085216.Google Scholar]. At that time, Intervet (➔ SP-Intervet and today MSD AH) joined forces with Nissan to discover the ectoparasiticide potential and molecular mode of action of what is known today as fluralaner [33.Heckeroth, A.R. et al. Intervet Int. BV, (2009). Isoxazoline compositions and their use as antiparasitics. WO2009024541.Google Scholar]. DuPont followed with patents on afoxolaner in 2009, which was subsequently developed by Merial (now Boehringer Ingelheim AH) [34.Lahm, G.P. et al. E. I. du Pont de Nemours and Company, (2009). Naphthalene isoxazoline invertebrate pest control agents. WO2009002809.Google Scholar]. Inspired by these activities, Pfizer (today Zoetis, and independent of Pfizer) initiated their internal isoxazoline program in 2009, synthesizing and developing sarolaner [35.Billen, D. et al., Zoetis LLC, (2012). Spirocyclic isoxazoline derivatives as antiparasitic agents. WO2012120399.Google Scholar]. Ely Lilly's Animal Health business, Elanco (today independent of Ely Lilly), last to enter the scene, collaborated with the medicinal chemical company Anacor (later acquired by Pfizer) for the synthesis of respective isoxazolines. Although Anacor successfully delivered on the goal, Elanco developed lotilaner, patented first by Novartis AH and acquired as a result of the takeover of Novartis Animal Health in 2015 [36.Nanchen, S. et al. Novartis AG, (2010). Isoxazoline derivatives and their use as pesticide. WO2010070068.Google Scholar]. Bayer AH followed with an as-yet unmarketed isoxazoline (international nonproprietary name – INN – tigolaner, received in 2017ix, which originated from Bayer Crop Science [37.Maue, M. et al. Bayer Cropscience Aktiengesellschaft, (2014). Halogen-substituted pyrazole derivatives as pest-control agents. WO2014122083Google Scholar]. Elanco finalized the acquisition of Bayer AH in August 2020 as a consequence of the takeover of Monsanto by Bayer Crop Sciencevii,viii (see Figure 2 in main text). It has been demonstrated that the (S)-enantiomer of the isoxazolines is the active component, whereas the (R)-enantiomer is inactive [18.Ozoe Y. et al.The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.Biochem. Biophys. Res. Commun. 2010; 391: 744-749Crossref PubMed Scopus (166) Google Scholar]. Nexgard® [11.Shoop W.L. et al.Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.Vet. Parasitol. 2014; 201: 179-189Crossref PubMed Scopus (122) Google Scholar,12.Xu M. et al.The discovery of afoxolaner: a new ectoparasiticide for dogs.in: Meng C.Q. Sluder A.E. Ectoparasites: Drug Discovery Against Moving Targets. Wiley-VCH, 2018: 259-271Crossref Scopus (3) Google Scholar] and Bravecto® [14.Gassel M. et al.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: 111-124Crossref PubMed Scopus (160) Google Scholar] were the first marketed products in 2014 using the respective racemate afoxolaner and fluralaner as first-generation isoxazoline active APIs [7.Weber T. Selzer P.M. Isoxazolines: a novel chemotype highly effective on ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref PubMed Scopus (58) Google Scholar]. These products provided much-needed breakthrough innovation, not only related to the new class but also with the oral administration in a market dominated by topical spot-ons. Isolating the active (S)-enantiomer would have required additional years, significantly delaying the introduction of such innovation into the market. Simparica® (market entry in 2016) [15.McTier T.L. et al.Discovery of sarolaner: a novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.Vet. Parasitol. 2016; 222: 3-11Crossref PubMed Scopus (85) Google Scholar] and Credelio® (market entry in 2018) [17.Rufener L. et al.The novel isoxazoline ectoparasiticide lotilaner (CredelioTM): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls).Parasit. Vectors. 2017; 10: 530Crossref PubMed Scopus (24) Google Scholar] followed into the market several years later, containing the isolated (S)-enantiomer in the product. It is noticeable that the oral route of administration in dogs brought new benefits, particularly increased customer convenience but also the reduced potential for owner exposure to the compound(s). The isoxazolines have been shown to circumvent cross-resistance by targeting a distinct new binding pocket in the chloride channels, setting the stage for an innovative new approach to tackling ectoparasitic infestations, which has thus far led to the approval of four orally administered veterinary products against ectoparasites on dogs. In addition, combination products, such as NexGard Spectra® (afoxolaner + milbemycin) [19.Beugnet F. et al.Evaluation of the efficacy of monthly oral administration of afoxolaner plus milbemycin oxime (NexGard Spectra(®), Merial) in the prevention of adult Spirocerca lupi establishment in experimentally infected dogs.Vet. Parasitol. 2016; 226: 150-161Crossref PubMed Scopus (6) Google Scholar] and Simparica Trio® (sarolaner + moxidectin + pyrantel) [20.Becskei C. et al.Efficacy of a novel oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against natural flea and tick infestations on dogs presented as veterinary patients in Europe.Parasit. Vectors. 2020; 13Google Scholar], have been launched. In view of these developments, further derivatives and combinations are certainly in the pipelines to fully explore the isoxazoline scaffold's potential. Following these successful products for dogs, isoxazoline formulations have been launched recently for use in cats. These are topical products which are easier to administer to cats as compared with oral products. They may contain isoxazolines alone (e.g., Bravecto® spot-on for cats, fluralaner), or in combination (e.g., Bravecto Plus® for cats, fluralaner + moxidectin; Stronghold Plus®, sarolaner + selamectin) [21.Becskei C. et al.Speed of kill of a new spot-on formulation of selamectin plus sarolaner for cats against induced infestations with Ixodes ricinus.Vet. Parasitol. 2017; 238: S8-S11Crossref PubMed Scopus (9) Google Scholar,22.Taenzler J. et al.Efficacy of fluralaner plus moxidectin (Bravecto® Plus spot-on solution for cats) against Otodectes cynotis infestations in cats.Parasit. Vectors. 2018; 11: 595Crossref PubMed Scopus (8) Google Scholar]. Isoxazolines also have potential for the development of long-acting formulations, providing more than the current 1 or 3 months of flea and tick control. Finally, isoxazolines have brought real innovation in treating mite infestations such as sarcoptic mange [23.Beugnet F. et al.Efficacy of afoxolaner in a clinical field study in dogs naturally infested with Sarcoptes scabiei.Parasite. 2016; 23: 26Crossref PubMed Scopus (35) Google Scholar] and demodicosis in dogs [24.Beugnet F. et al.Efficacy of oral afoxolaner for the treatment of canine generalised demodicosis.Parasite. 2016; 23: 14Crossref PubMed Scopus (51) Google Scholar], ear mange in cats [22.Taenzler J. et al.Efficacy of fluralaner plus moxidectin (Bravecto® Plus spot-on solution for cats) against Otodectes cynotis infestations in cats.Parasit. Vectors. 2018; 11: 595Crossref PubMed Scopus (8) Google Scholar,25.Vatta A.F. et al.Efficacy and safety of a combination of selamectin plus sarolaner for the treatment and prevention of flea infestations and the treatment of ear mites in cats presented as veterinary patients in the United States.Vet. Parasitol. 2019; 270: S3-S11Crossref PubMed Scopus (10) Google Scholar], and Dermanyssus in poultry [26.Brauneis M.D. et al.The acaricidal speed of kill of orally administered fluralaner against poultry red mites (Dermanyssus gallinae) on laying hens and its impact on mite reproduction.Parasit. Vectors. 2017; 10: 1-8Crossref PubMed Scopus (18) Google Scholar]. Their insecticidal activity has also been demonstrated on blood-feeding dipterans, such as mosquitoes [27.Liebenberg J. et al.Assessment of the insecticidal activity of afoxolaner against Aedes aegypti in dogs treated with NexGard®.Parasite. 2017; 24: 39Crossref PubMed Scopus (9) Google Scholar] and sandflies [28.Perier N. et al.Assessment of the insecticidal activity of oral afoxolaner against Phlebotomus perniciosus in dogs.Parasite. 2019; 26: 63Crossref PubMed Scopus (5) Google Scholar], allowing new usage to control arthropod vectors. As with other compounds initially launched with a veterinary application – for example, benzimidazoles, praziquantel, and ivermectin [8.Geary T.G. et al.Target identification and mechanism-based screening for anthelmintics: application of veterinary antiparasitic research programs to search for new antiparasitic drugs for human indications.in: Selzer P.M. Antiparasitic and Antibacterial Drug Discovery. Wiley-VCH, 2009: 3-15Crossref Scopus (25) Google Scholar] – isoxazolines appear to have potential for development in other species, including humans. In human-host parasitology applications, they also may be active against several insects, mites, lice, and ticks [7.Weber T. Selzer P.M. Isoxazolines: a novel chemotype highly effective on ectoparasites.ChemMedChem. 2016; 11: 270-276Crossref PubMed Scopus (58) Google Scholar,29.Miglianico M. et al.Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E6920-E6926Crossref PubMed Scopus (35) Google Scholar]. Afoxolaner efficacy has been demonstrated in swine as a model of human sarcoptic mange [30.Bernigaud C. et al.Efficacy and pharmacokinetic evaluation of a single oral dose of afoxolaner against Sarcoptes scabiei in the porcine scabies model for human infestation.Antimicrob. Agents Chemother. 2018; 62e02334-17Crossref PubMed Scopus (14) Google Scholar]. If so, isoxazolines might also be able to impede arthropod-borne diseases, such as Lyme disease, as demonstrated in dogs [31.Baker C.F. et al.Ability of an oral formulation of afoxolaner to protect dogs from Borrelia burgdorferi infection transmitted by wild Ixodes scapularis ticks.Comp. Immunol. Microbiol. Infect. Dis. 2016; 49: 65-69Crossref PubMed Scopus (10) Google Scholar], or even neglected tropical diseases of humans, such as human African trypanosomiosis (sleeping sickness), leishmaniosis, and malaria, for which respective claims have already been made in the patent literature [32.Mita, T. et al. Nissan Chemical Industries, Ltd., Japan, (2005). Isoxazoline‐substituted benzamide compound and noxious organism control agent. WO2005085216.Google Scholar, 33.Heckeroth, A.R. et al. Intervet Int. BV, (2009). Isoxazoline compositions and their use as antiparasitics. WO2009024541.Google Scholar, 34.Lahm, G.P. et al. E. I. du Pont de Nemours and Company, (2009). Naphthalene isoxazoline invertebrate pest control agents. WO2009002809.Google Scholar, 35.Billen, D. et al.