Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases

Abstract

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 ,, and mosquitoes and sand flies after feeding on a drug-supplemented blood meal, with IC 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 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.

Optimizing systemic insecticide use to improve malaria control

“…The relationship between mosquito fecundity or mortality and the concentration of LLINs or systemic insecticides is not linear, but is captured by Hill kinetics. The F 50 , , and Hill coefficients ( H b and H d for birth and death rates, respectively) were calculated for lab-reared Anopheles for different systemic insecticides by fitting a Hill equation to published data (27–29) ( Fig. S1-2 ).…”

“…The was calculated for wild Anopheles that displayed a range of resistance to LLINs and the Hill coefficient ( H n ) was calculated for lab-reared, permethrin resistant Anopheles by fitting a Hill equation to published data (30, 31). The time window ( T N or T D ) associated with each insecticide’s LC 50 was based on previously reported measurements (27–29, 31).…”

Evolution of the insecticide targetRdlin AfricanAnophelesis driven by interspecific and interkaryotypic introgression

“…Other possible factors behind the persistence of Rdl resistance alleles include the long half-life of dieldrin as an environmental organic pollutant; as well as the fact that Rdl is the target site of other insecticides such as fipronil, isoxazoline or meta-diamides (Gant et al 1998;Nakao and Banba 2015;Miglianico et al 2018); a secondary target of avermectin (Miglianico et al 2018), and, possibly, of neonicotinoids (imidacloprid), pyrethroids (deltamethrin) (Taylor-Wells et al…”

“…This evolutionary trajectory has parallels with later-emerging target site resistance mutations, such as Vgsc (Martinez-Torres et al 1998; Davies et al 2007;Clarkson et al 2014;Clarkson et al 2018). The persistence of dieldrin resistance also challenges the efficacy of current and newly developed insecticides that also target Rdl (Gant et al 1998;Nakao and Banba 2015;Miglianico et al 2018), as well as the efficacy of rotative insecticide management strategies (World Health Organization 2012). These results thus emphasise the influence of past interventions on current and future programmes of vector population control.…”

Reducing malaria burden and accelerating elimination with long-lasting systemic insecticides: a modeling study of three potential use cases

“…A recent study in Burkina Faso observed a 20% reduction in clinical incidence in an intervention group receiving ivermectin 6 times over 18 weeks at 3 week intervals, with young children, pregnant women, and women nursing newborns excluded from MDA eligibility [16]. Another drug class, isoxazolines, shows promise to maintain mosquitocidal activity up to 50-90 days [17], although safety concerns still need to be addressed [18].…”