Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.

California Institute for Biomedical Research La Jolla CA 92037

California Institute for Biomedical Research La Jolla CA 92037;

Department of Medical Microbiology Radboud University Medical Center 6525 Nijmegen The Netherlands

Department of Parasitology Faculty of Science Charles University 116 36 Prague Czech Republic

Laboratory of Entomology Wageningen University and Research 6700 Wageningen The Netherlands

MRC Centre for Outbreak Analysis and Modelling Department of Infectious Disease Epidemiology Imperial College London London SW7 2AZ United Kingdom

Numerus Ltd RG40 2AY Tübingen Germany

The Liverpool Insect Testing Establishment Liverpool School of Tropical Medicine Liverpool L3 5QA United Kingdom

TropIQ Health Sciences 6534 Nijmegen The Netherlands

TropIQ Health Sciences 6534 Nijmegen The Netherlands;

XenoGesis Ltd Nottingham NG1 1GF United Kingdom

Zobrazit více v PubMed

Benelli G, Mehlhorn H. Declining malaria, rising of dengue and Zika virus: Insights for mosquito vector control. Parasitol Res. 2016;115:1747–1754. PubMed

Maroli M, Feliciangeli MD, Bichaud L, Charrel RN, Gradoni L. Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. Med Vet Entomol. 2013;27:123–147. PubMed

Rizzoli A, et al. The challenge of West Nile virus in Europe: Knowledge gaps and research priorities. Euro Surveill. 2015;20:21135. PubMed

Bhatt S, et al. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015;526:207–211. PubMed PMC

Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374:1552–1563. PubMed

Foy BD, Kobylinski KC, da Silva IM, Rasgon JL, Sylla M. Endectocides for malaria control. Trends Parasitol. 2011;27:423–428. PubMed PMC

Govella NJ, Ferguson H. Why use of interventions targeting outdoor biting mosquitoes will be necessary to achieve malaria elimination. Front Physiol. 2012;3:199. PubMed PMC

Franco AO, Gomes MG, Rowland M, Coleman PG, Davies CR. Controlling malaria using livestock-based interventions: A one health approach. PLoS One. 2014;9:e101699. PubMed PMC

Bellinger AM, et al. Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals. Sci Transl Med. 2016;8:365ra157. PubMed PMC

Shoop WL, et al. Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs. Vet Parasitol. 2014;201:179–189. PubMed

Gassel M, Wolf C, Noack S, Williams H, Ilg T. The novel isoxazoline ectoparasiticide fluralaner: Selective inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/acaricidal activity. Insect Biochem Mol Biol. 2014;45:111–124. PubMed

Letendre L, et al. The intravenous and oral pharmacokinetics of afoxolaner used as a monthly chewable antiparasitic for dogs. Vet Parasitol. 2014;201:190–197. PubMed

Walther FM, Allan MJ, Roepke RK. Plasma pharmacokinetic profile of fluralaner (Bravecto) and ivermectin following concurrent administration to dogs. Parasit Vectors. 2015;8:508. PubMed PMC

Walther FM, Paul AJ, Allan MJ, Roepke RK, Nuernberger MC. Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(−/−) collies after oral administration. Parasit Vectors. 2014;7:86. PubMed PMC

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;391:744–749. PubMed

Casida JE, Durkin KA. Novel GABA receptor pesticide targets. Pestic Biochem Physiol. 2015;121:22–30. PubMed

Weber T, Selzer PM. Isoxazolines: A novel chemotype highly effective on ectoparasites. ChemMedChem. 2016;11:270–276. PubMed

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. PubMed PMC

Ferguson NM, et al. Countering the Zika epidemic in Latin America. Science. 2016;353:353–354. PubMed PMC

Netto EM, et al. High Zika virus seroprevalence in Salvador, northeastern Brazil limits the potential for further outbreaks. MBio. 2017;8:e01390-17. PubMed PMC

Saba Villarroel PM, et al. Zika virus epidemiology in Bolivia: A seroprevalence study in volunteer blood donors. PLoS Negl Trop Dis. 2018;12:e0006239. PubMed PMC

Burkot T, Ichimori K. The PacELF programme: Will mass drug administration be enough? Trends Parasitol. 2002;18:109–115. PubMed

Cheah PY, White NJ. Antimalarial mass drug administration: Ethical considerations. Int Health. 2016;8:235–238. PubMed PMC

Slater HC, Walker PG, Bousema T, Okell LC, Ghani AC. The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: A modelling study. J Infect Dis. 2014;210:1972–1980. PubMed

Walker PG, Griffin JT, Ferguson NM, Ghani AC. Estimating the most efficient allocation of interventions to achieve reductions in Plasmodium falciparum malaria burden and transmission in Africa: A modelling study. Lancet Glob Health. 2016;4:e474–e484. PubMed

Hamilton M, et al. Spectrum-malaria: A user-friendly projection tool for health impact assessment and strategic planning by malaria control programmes in sub-Saharan Africa. Malar J. 2017;16:68. PubMed PMC

Brady OJ, et al. Role of mass drug administration in elimination of Plasmodium falciparum malaria: A consensus modelling study. Lancet Glob Health. 2017;5:e680–e687. PubMed PMC

WHO Global Malaria Programme . World Malaria Report. World Health Organization; Geneva, Switzerland: 2015.

Cairns M, et al. Estimating the potential public health impact of seasonal malaria chemoprevention in African children. Nat Commun. 2012;3:881. PubMed PMC

European Medicines Agency, Committee for Medicinal Products for Veterinary Use 2016 CVMP assessment report for Bravecto for spot-on solution for dogs and cats. Available at www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/veterinary/002526/WC500163860.pdf. Accessed June 11, 2018.

U.S. Food and Drug Administration 2014 Corrected Freedom of Information Summary, NADA 141-426. Available at https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1502. Accessed June 11, 2018.

U.S. Food and Drug Administration 2014 Freedom of Information Summary, NADA 141-406. Available at https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/912. Accessed June 11, 2018.

Committee for Medicinal Products for Veterinary Use 2013. CVMP assessment report for NexGard (European Medicines Agency, London), EMEA/V/C/002729/0000.

Merial Australia Pty Ltd 2014 Safety data sheet: NexGard. Available at www.frontlineplus.com.au/resource_centre//files/pdf/SDS_Afoxolaner_2%2027_Chewable%20Tablets_Masked_Formulation_061313_Australia_241014.pdf. Accessed June 11, 2018.

US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 2005 Guide for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Available at https://www.fda.gov/downloads/Drugs/Guidance/UCM078932.pdf. Accessed June 11, 2018.

McTier TL, et al. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs. Vet Parasitol. 2016;222:3–11. PubMed

Chaccour C, Rabinovich NR. Ivermectin to reduce malaria transmission II: Considerations regarding clinical development pathway. Malar J. 2017;16:166. PubMed PMC

Alout H, Foy B. Ivermectin: A complementary weapon against the spread of malaria? Expert Rev Anti Infect Ther. 2016;15:231–240. PubMed PMC

Ouédraogo AL, et al. Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: A double-blind, randomized, clinical trial. Clin Infect Dis. 2015;60:357–365. PubMed

Kobylinski KC, et al. The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors. Acta Trop. 2010;116:119–126. PubMed PMC

Derua YA, Kisinza WN, Simonsen PE. Differential effect of human ivermectin treatment on blood feeding Anopheles gambiae and Culex quinquefasciatus. Parasit Vectors. 2015;8:130. PubMed PMC

Akhoundi M, et al. A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl Trop Dis. 2016;10:e0004349. PubMed PMC

Annis GD. 2009. E.I. Du Pont De Nemours and Company Patent Application WO 2009126668.

García-Reynaga P, Zhao C, Sarpong R, Casida JE. New GABA/glutamate receptor target for [3H]isoxazoline insecticide. Chem Res Toxicol. 2013;26:514–516. PubMed PMC

Feldmann AM, Ponnudurai T. Selection of Anopheles stephensi for refractoriness and susceptibility to Plasmodium falciparum. Med Vet Entomol. 1989;3:41–52. PubMed

Edi CV, Koudou BG, Jones CM, Weetman D, Ranson H. Multiple-insecticide resistance in Anopheles gambiae mosquitoes, southern Côte d’Ivoire. Emerg Infect Dis. 2012;18:1508–1511. PubMed PMC

Harris AF, Rajatileka S, Ranson H. Pyrethroid resistance in Aedes aegypti from Grand Cayman. Am J Trop Med Hyg. 2010;83:277–284. PubMed PMC

Vogels CB, Fros JJ, Göertz GP, Pijlman GP, Koenraadt CJ. Vector competence of northern European Culex pipiens biotypes and hybrids for West Nile virus is differentially affected by temperature. Parasit Vectors. 2016;9:393. PubMed PMC

Ponnudurai T, et al. Infectivity of cultured Plasmodium falciparum gametocytes to mosquitoes. Parasitology. 1989;98:165–173. PubMed

Volf P, Volfova V. Establishment and maintenance of sand fly colonies. J Vector Ecol. 2011;36(Suppl 1):S1–S9. PubMed

WHO Pesticide Evaluation Scheme . Test Procedures for Insecticide Resistance Monitoring in Malaria Vectors, Bio-Efficacy and Persistence of Insecticides on Treated Surfaces. World Health Organization; Geneva, Switzerland: 1998.

Fipronil prevents transmission of Lyme disease spirochetes