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Ivermectin metabolites reduce Anopheles survival.

ABSTRACT: 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 LC₅₀ nor LC₉₀ 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.

SUBMITTER: Kobylinski KC

PROVIDER: S-EPMC10199058 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Ivermectin metabolites reduce Anopheles survival.

Kobylinski Kevin C KC Tipthara Phornpimon P Wamaket Narenrit N Chainarin Sittinont S Kullasakboonsri Rattawan R Sriwichai Patchara P Phasomkusolsil Siriporn S Hanboonkunupakarn Borimas B Jittamala Podjanee P Gemmell Renia R Boyle John J Wrigley Stephen S Steele Jonathan J White Nicholas J NJ Tarning Joel J

Scientific reports 20230519 1

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 ch ...[more]

PMID: 37208382

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Project description:BackgroundIvermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A "post-ivermectin effect" has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect.MethodsIvermectin was incubated in the presence of recombinant human cytochrome P450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (Cmax) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days.ResultsHuman CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1-M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H2B1a) was mainly produced by CYP3A5. Both desmethyl-H2B1a (M1) and hydroxy-H2B1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H2B1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at Cmax levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h).ConclusionIn conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the "post-ivermectin effect".

Project description:BackgroundNovel 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.MethodsA 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% (LC50) 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 LC25 or LC5 for An. dirus and An. minimus.ResultsThe GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC50 = 16.3 ng/ml) > An. campestris (LC50 = 26.4 ng/ml) = An. sawadwongporni (LC50 = 26.9 ng/ml) > An. dirus (LC50 = 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 LC25 and LC5 concentrations.ConclusionsIvermectin 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.

Project description:BackgroundMost malaria vector control programmes rely on indoor residual spraying of insecticides and insecticide-treated bed nets. This is effective against vector species that feed indoors at night and rest inside the house afterwards. In Central America, malaria vectors have different behaviours and are typically exophagic (i.e., bite outdoors), exophilic (i.e., remain outdoors after feeding), and zoophagic (i.e., as likely to feed on non-humans as humans). Thus, malaria elimination in Central America may require additional tactics. This pilot study investigated whether commercially-available products used to treat livestock for ticks could also be used to kill and/or sterilize zoophagic malaria vectors that feed on treated cattle in Belize.MethodsCattle were treated with either a pour-on formulation of 1% fipronil (3 heifers) or injection of 1% ivemectin (1 heifer). Control heifers (n = 2) were left untreated. Field-collected Anopheles albimanus contained in screen-top cages were strapped onto cattle at 2, 5, 7, and 14 days after treatment. Mosquito mortality was monitored once a day for 4 successive days. Surviving mosquitoes were dissected to assess blood meal digestion and ovarian development.ResultsA total of 1078 female An. albimanus mosquitoes were fed and monitored for mortality. Both fipronil and ivermectin significantly reduced survivorship of An. albimanus for up to 7 days after treatment. By 14 days, efficacy had declined. The ivermectin treatment completely lost its effectiveness and even though the fipronil-treated heifers were still killing significantly more mosquitoes than the untreated heifers, the amount of mosquito killing had diminished greatly. Both treatments significantly reduced ovary development in mosquitoes fed on treated cattle for the duration of the 2-week trial.ConclusionsTreatment of cattle in northern Belize with topical fipronil and injectable ivermectin had significant lethal and sublethal effects on wild An. albimanus females. These results suggest that efforts towards eliminating residual transmission of malaria by zoophagic vectors in Central America may benefit by the judicious, targeted treatment of livestock with mosquitocidal compounds, such as fipronil or ivermectin.

Project description:An increasing number of countries in sub-Saharan Africa are moving towards malaria-elimination, mostly thanks to successful vector control campaigns. However, elimination has proven challenging, resulting in the persistence of malaria transmission. It is now accepted that in order to eliminate malaria, new complementary vector control approaches must be developed. This study describes the development of a sugar-baited resting place containing a toxic dose of ivermectin for the control of Anopheles arabiensis.Dose response experiments were performed in insectary conditions to determine the LD90 of ivermectin against An. arabiensis. Over 95% of An. arabiensis were knocked down 48 h post-sugar feeding on 10% sucrose solutions containing 0.01% ivermectin. When investigating different juices as attractants, it was observed that An. arabiensis preferred orange, watermelon and commercial guava juice over pawpaw, tomato, mango or banana, but were most likely to feed on simple 10% sugar solution. Using recycled materials, different bait prototypes were tested to determine the best design to maximize sugar feeding. Baits that offered a resting place for the mosquito rather than just a surface to sugar feed were more likely to attract An. arabiensis to sugar feed. The optimized prototype was then placed in different locations within a screen-house, colour-coded with different food dyes, containing competing vegetation (Ricinus communis) and experimental huts where humans slept under bed nets. Around half of all the released An. arabiensis sugar fed on the sugar baits, and approximately 50% of all sugar fed mosquitoes chose the baits close to outdoor vegetation before entering the huts.Ivermectin is an effective insecticide for use in sugar baits. The design of the sugar bait can influence feeding rates and, therefore, efficacy. Sugar baits that offer a resting surface are more efficient and sugar feeding on the baits is maximized when these are placed close to peri-domestic vegetation. Attractive toxic sugar baited resting places may provide an additional vector control method to complement with existing strategies.

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Ivermectin metabolites reduce Anopheles survival.

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Ivermectin metabolites reduce Anopheles survival.

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