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Background Ivermectin is lethal to Anopheles mosquitoes and a novel approach to malaria transmission control. Ivermectin could be co-administered with antimalarial drugs in mass drug administration, seasonal malaria chemoprevention, or other chemoprevention approaches. Co-administration with antimalarial drugs may impact ivermectin metabolism and/or absorption, resulting in increased or decreased exposure to ivermectin. Methods To evaluate potential CYP-mediated drug-drug interactions (DDIs), ivermectin (1 µM) was incubated with pooled human liver microsomes, with and without the most commonly used antimalarial drugs at concentrations approximating twofold to tenfold the peak concentrations achieved following standard treatment. The antimalarial drugs investigated were dihydroartemisinin, piperaquine, chloroquine, artesunate, pyronaridine, mefloquine, artemether, lumefantrine, primaquine, atovaquone, proguanil, tafenoquine, sulfadoxine, pyrimethamine, and amodiaquine. Samples (50 µL) were collected at 0, 15, 30, 45, 60, 90, 120, and 150 min of incubation and ivermectin concentrations were measured using liquid chromatography-mass spectrometry. The metabolism rate of ivermectin was evaluated based on the normalized peak area (%) of ivermectin over a total of 150 min of incubation, applying linear regression to derive the rate of metabolism. Antimalarial compounds resulting in notable impact on the rate of ivermectin metabolism with a relative difference ≥ 50% and ≥ 25% were considered to have a substantial and partial effect on the in vitro metabolism of ivermectin, respectively. Results Compounds that had a substantial DDI effect on the in vitro metabolism of ivermectin included piperaquine (98%), mefloquine (91%), chloroquine (76%), proguanil (60%), and lumefantrine (51%). Compounds that a partial DDI effect on the in vitro metabolism of ivermectin included atovaquone (48%), artesunate (27%), and pyronaridine (25%). All other antimalarials evaluated showed an in vitro interaction of 8–23%. Conclusions Several of the commonly used antimalarial drugs, are mostly or in part metabolized by CYP3A4 and showed a notable DDI effect on the in vitro metabolism of ivermectin. This could potentially lead to clinically important pharmacokinetic and pharmacodynamic DDIs if co-administered, and needs to be evaluated in prospective clinical trials.

Background When ingested in a blood meal, ivermectin has been shown to reduce the survivorship of Anopheles gambiae in the laboratory and field. Furthermore, ivermectin mass drug administrations in Senegal have been shown to reduce the proportion of Plasmodium falciparum -sporozoite-containing An. gambiae . This study addresses whether ivermectin inhibits sporogony of P. falciparum in An. gambiae. Methods Anophele gambiae s.s. G3 strain were fed two concentrations of ivermectin (LC 25 and LC 5 ) along with P. falciparum NF54 in human blood meals at staggered intervals. Mosquitoes ingested ivermectin concurrent with parasites (DPI 0), or at three (DPI 3), six (DPI 6), and nine (DPI 9) days post parasite ingestion, or three days prior (DPI −3) to parasite ingestion. Mosquitoes were dissected at seven, twelve or fourteen days post parasite ingestion and either oocyst or sporozoite prevalence was recorded. To determine if P. falciparum sporozoite-containing An. gambiae were more susceptible to ivermectin than uninfected controls, survivorship was recorded for mosquitoes which ingested P. falciparum or control blood meal on DPI 0 and then a second blood meal containing ivermectin (LC 25 ) on DPI 14. Results Ivermectin (LC 25 ) co-ingested (DPI 0) with parasites reduced the proportion of An. gambiae that developed oocysts ( χ 2 = 15.4842, P = 0.0002) and sporozoites ( χ 2 = 19.9643, P < 0.0001). Ivermectin (LC 25 ) ingested DPI 6 ( χ 2 = 8.5103, P = 0.0044) and 9 ( χ 2 = 14.7998, P < 0.0001) reduced the proportion of An. gambiae that developed sporozoites but not when ingested DPI 3 ( χ 2 = 0.0113, P = 1). Ivermectin (LC 5 ) co-ingested (DPI 0) with parasites did not reduce the proportion of An. gambiae that developed oocysts ( χ 2 = 4.2518, P = 0.0577) or sporozoites ( χ 2 = 2.3636, P = 0.1540), however, when ingested DPI −3 the proportion of An. gambiae that developed sporozoites was reduced ( χ 2 = 8.4806, P = 0.0047). Plasmodium falciparum infection significantly reduced the survivorship of An. gambiae that ingested ivermectin (LC 25 ) on DPI 14 compared to control mosquitoes that ingested a primary blood meal without parasites ( χ 2 = 4.97, P = 0.0257). Conclusions Ivermectin at sub-lethal concentrations inhibits the sporogony of P. falciparum in An. gambiae . These findings support the utility of ivermectin for P. falciparum transmission control.

Background Emodepside is an anthelmintic used in veterinary medicine that is currently under investigation in human clinical trials for the treatment of soil-transmitted helminths and possibly Onchocerca volvulus . Emodepside targets the calcium-activated voltage-gated potassium slowpoke 1 (SLO-1) channels of presynaptic nerves of pharynx and body wall muscle cells of nematodes leading to paralysis, reduced locomotion and egg laying, starvation, and death. Emodepside also has activity against Drosophila melanogaster SLO-1 channels. Orthologous SLO-1 genes are present in Anopheles gambiae and Aedes aegypti , suggesting that emodepside may have activity against mosquitoes. Methods Both Anopheles dirus and Ae. aegypti were blood-fed emodepside across a range of concentrations (1–10,000 nM) and mosquito survival was monitored for 10 days. Co-feeding experiments were also performed with An. dirus blood fed ivermectin at the concentrations that kills 25% (LC 25 ) and 50% (LC 50 ) of mosquitoes with and without emodepside at clinical peak concentration in humans (C max ) and five times the C max , and mosquito survival was monitored for 10 days. Results Emodepside had weak mosquito-lethal effects in An. dirus but none observed in Ae. aegypti at the concentrations evaluated. The An. dirus emodepside LC 50 was 4,623 [4,159–5,066] ng/ml which is > 100-fold greater than the peak concentrations seen in human. The ivermectin and emodepside co-feed experiment with An. dirus did not indicate any altered effect of ivermectin on mosquito survival when emodepside co-fed at human C max or five times that of the human C max . Conclusions Emodepside was not lethal to An. dirus at human-relevant concentrations and had no effect on Ae. aegypti survival. Thus, mass distribution of emodepside does not appear to be a potential tool for vector-borne disease control. Emodepside induced mortality in An. dirus does suggest that the SLO-1 channel could be a potential target for novel vector control and may warrant further investigation.

Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. The mosquito-lethal effect of ivermectin in clinical trials exceeds that predicted from in vitro laboratory experiments, suggesting that ivermectin metabolites have mosquito-lethal effect. The three primary ivermectin metabolites in humans ( i.e ., M1 (3″- O -demethyl ivermectin), M3 (4-hydroxymethyl ivermectin), and M6 (3″- O -demethyl, 4-hydroxymethyl ivermectin) were obtained by chemical synthesis or bacterial modification/metabolism. Ivermectin and its metabolites were mixed in human blood at various concentrations, blood-fed to Anopheles dirus and Anopheles minimus mosquitoes, and mortality was observed daily for fourteen days. Ivermectin and metabolite concentrations were quantified by liquid chromatography linked with tandem mass spectrometry to confirm the concentrations in the blood matrix. Results revealed that neither the LC 50 nor LC 90 values differed between ivermectin and its major metabolites for An. dirus or An. minimus. , Additionally, there was no substantial differences in the time to median mosquito mortality when comparing ivermectin and its metabolites, demonstrating an equal rate of mosquito killing between the compounds evaluated. These results demonstrate that ivermectin metabolites have a mosquito-lethal effect equal to the parent compound, contributing to Anopheles mortality after treatment of humans.

Background The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve. Most of the current vector control measures insufficiently target outdoor transmission. Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets. Innovative approaches are needed. The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures. Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis. Methods The previous works involving ivermectin and Anopheles vectors are reviewed and summarized. A review of ivermectin’s safety profile is also provided. Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation. Several smaller and specific supportive studies are also proposed. Conclusions The use of ivermectin solves many challenges identified for future vector control strategies. It is an effective and safe endectocide that was approved for human use more than 25 years ago. Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality.

The mosquito-lethal effect of commercially available standard and long-lasting ivermectin formulations were evaluated in cattle and buffalo against wild-caught Anopheles on Sumba Island, Indonesia. Cattle have substantially higher blood-level concentrations of ivermectin compared to buffalo after receiving similar doses, irrespective of formulation. In total, nine Anopheles species were captured to assess the mosquito-lethal effects of ivermectin with susceptibility ranked from lowest to highest: An. flavirostris  <  An. aconitus  <  An. annularis  <  An. tessellatus  <  An. maculatus  <  An. sundaicus  <  An. vagus  <  An. kochi  <  An. barbirostris. The duration of mosquito-lethal effect of long-lasting ivermectin was superior to standard ivermectin and in cattle it well exceeded the WHO criteria for new endectocides having a mortality hazard ratio greater than 4 through 30 days after administration. Buffalo may require higher doses of long-lasting ivermectin to achieve similar mosquito-lethal effects observed in cattle. Of the four hosts evaluated buffalo were the most attractive to Anopheles followed by cattle then horse and finally humans. This study demonstrates, for the first time, the superiority of a commercially available long-lasting ivermectin formulation for the potential deployment of mass ivermectin treatment of livestock as a vector control tool for malaria elimination in Southeast Asia.

Background Novel vector control methods that can directly target outdoor malaria transmission are urgently needed in the Greater Mekong Subregion (GMS) to accelerate malaria elimination and artemisinin resistance containment efforts. Ivermectin mass drug administration (MDA) to humans has been shown to effectively kill wild Anopheles and suppress malaria transmission in West Africa. Preliminary laboratory investigations were performed to determine ivermectin susceptibility and sporontocidal effect in GMS Anopheles malaria vectors coupled with pharmacokinetic models of ivermectin at escalating doses. Methods A population-based pharmacokinetic model of ivermectin was developed using pre-existing data from a clinical trial conducted in Thai volunteers at the 200 µg/kg dose. To assess ivermectin susceptibility, various concentrations of ivermectin compound were mixed in human blood meals and blood-fed to Anopheles dirus , Anopheles minimus , Anopheles sawadwongporni , and Anopheles campestris . Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with probit analyses was used to calculate concentrations of ivermectin that killed 50% (LC 50 ) of mosquitoes for each species. Blood samples were collected from Plasmodium vivax positive patients and offered to mosquitoes with or without ivermectin at the ivermectin LC 25 or LC 5 for An. dirus and An. minimus . Results The GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC 50  = 16.3 ng/ml) >  An. campestris (LC 50  = 26.4 ng/ml) =  An. sawadwongporni (LC 50  = 26.9 ng/ml) >  An. dirus (LC 50  = 55.6 ng/ml). Mosquito survivorship results, the pharmacokinetic model, and extensive safety data indicated that ivermectin 400 µg/kg is the ideal minimal dose for MDA in the GMS for malaria parasite transmission control. Ivermectin compound was sporontocidal to P. vivax in both An. dirus and An. minimus at the LC 25 and LC 5 concentrations. Conclusions Ivermectin is lethal to dominant GMS Anopheles malaria vectors and inhibits sporogony of P. vivax at safe human relevant concentrations. The data suggest that ivermectin MDA has potential in the GMS as a vector and transmission blocking control tool to aid malaria elimination efforts.

Background Mass endectocide or ectocide treatment of humans or livestock has been suggested as a possible malaria vector control tool. This work provides guidance for in vitro endectocide and ectocide experiments and raises biological points for further evaluation. Methods Three experiments with ivermectin were performed with Anopheles dirus and Anopheles minimus . The first experiment assessed the impact of a sugar diet (10% sucrose, “ Sucrose ”; multivitamin syrup, “ Multivitamin ”; or multivitamin syrup followed by 10% sucrose, “ Mix ”) on mosquito mortality following ingestion of a range of ivermectin-spiked blood meal concentrations. The lethal concentrations that kill 50% (LC 50 ) and 90% (LC 90 ) of mosquitoes were estimated using a normalized concentration–response analysis (IC 50 and Hill slope). The second experiment assessed the impact on mosquito mortality after ingesting ivermectin spiked into a plasma meal or a blood meal that was either fresh or previously frozen. Log-rank survival curve analysis (Mantel–Cox method) was used to compare mosquito survival between groups. The third experiment sought to quantify the concentration of ivermectin in a blood meal compared to the amount imbibed into the mosquito midgut as measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results The Multivitamin diet was found to substantially increase An. dirus LC 50 compared to Sucrose and Mix diets, while the Sucrose diet had reduced control survival post-blood meal for both An. dirus and An. minimus . Ivermectin mortality response was substantially increased when ingested in a blood meal compared to a plasma meal for An. dirus , while the inverse was observed for An. minimus . For both An. dirus and An. minimus , an approximately 20% loss in ivermectin concentration was observed in the midgut compared to the blood meal. Conclusions The Mix diet appears to be best for minimizing control mosquito mortality, without altering the mosquito survival response following ivermectin ingestion. An unexplained biological phenomenon occurred when ivermectin was ingested in either a blood meal or a plasma meal. The concentration of ivermectin imbibed by the mosquito was lower than that observed in the blood meal, suggesting that some of the ivermectin may be excreted by the mosquito during the blood meal. Graphical Abstract