Efficacy and Safety of the Mosquitocidal Drug Ivermectin to Prevent Malaria Transmission After Treatment: A Double-Blind, Randomized, Clinical Trial

Ouédraogo, André Lin; Bastiaens, Guido J. H.; Tiono, Alfred B.; Guelbéogo, Wamdaogo Moussa; Kobylinski, Kevin C.; Ouédraogo, Alphonse; Barry, Aïssata; Bougouma, Edith C.; Nébié, Issa; Ouattara, Maurice S.; Lanke, Kjerstin; Fleckenstein, Lawrence; Sauerwein, Robert W.; Slater, Hannah; Churcher, Thomas S.; Sirima, Sodiomon B.; Drakeley, Chris; Bousema, Teun

doi:10.1093/cid/ciu797

Cited by 105 publications

(128 citation statements)

References 24 publications

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“…A threshold of 7 ng/ml was used as target because it is the lowest determined LC 50 for An. gambiae [30]. There is need for a clear determination of the in vivo LC 50 for the main vector species.…”

Section: Discussionmentioning

confidence: 99%

“…The LC 50 estimated with this method ranges from 14.6 to 26.9 ng/ml [22,28]. Recent evidence from membrane feedings using blood drawn from ivermectin treated volunteers gives a much lower range of 4.69-7.51 ng/ml [30]. This discrepancy could be the result of unknown active metabolites and possibly, blood meal size differences between membrane and skin feeding mosquitoes.…”

Section: Introductionmentioning

confidence: 99%

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Screening for an ivermectin slow-release formulation suitable for malaria vector control

Chaccour

Barrio

Royo

et al. 2015

Malar J

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BackgroundThe prospect of eliminating malaria is challenged by emerging insecticide resistance and vectors with outdoor and/or crepuscular activity. Ivermectin can simultaneously tackle these issues by killing mosquitoes feeding on treated animals and humans. A single oral dose, however, confers only short-lived mosquitocidal plasma levels.MethodsThree different slow-release formulations of ivermectin were screened for their capacity to sustain mosquito-killing levels of ivermectin for months. Thirty rabbits received a dose of one, two or three silicone implants containing different proportions of ivermectin, deoxycholate and sucrose. Animals were checked for toxicity and ivermectin was quantified periodically in blood. Potential impact of corresponding long-lasting formulation was mathematically modelled.ResultsAll combinations of formulation and dose released ivermectin for more than 12 weeks; four combinations sustained plasma levels capable of killing 50% of Anopheles gambiae feeding on a treated subject for up to 24 weeks. No major adverse effects attributable to the drug were found. Modelling predicts a 98% reduction in infectious vector density by using an ivermectin formulation with a 12-week duration.ConclusionsThese results indicate that relatively stable mosquitocidal plasma levels of ivermectin can be safely sustained in rabbits for up to six months using a silicone-based subcutaneous formulation. Modifying the formulation of ivermectin promises to be a suitable strategy for malaria vector control.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0618-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening for an ivermectin slow-release formulation suitable for malaria vector control

Chaccour

Barrio

Royo

et al. 2015

Malar J

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“…Sub-lethal doses of IVM have also been shown to inhibit the sporogony of P. falciparum in A. gambiae s.s. and impair coordinated flight patterns (Butters et al, 2012;Kobylinski et al, 2012). In clinical trials, IVM, in combination with artemether-lumefantrine, has been shown to reduce the likelihood of malaria transmission through reduction of mosquito survivorship (Ouedraogo et al, 2014). These studies demonstrate that IVM has promise as a novel malaria control tool.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

Meyers

Gray

Kuklinski

et al. 2015

Journal of Experimental Biology

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The use of insecticide-treated nets and indoor residual insecticides targeting adult mosquito vectors is a key element in malaria control programs. However, mosquito resistance to the insecticides used in these applications threatens malaria control efforts. Recently, the mass drug administration of ivermectin (IVM) has been shown to kill Anopheles gambiae mosquitoes and disrupt Plasmodium falciparum transmission in the field. We cloned the molecular target of IVM from A. gambiae, the glutamate-gated chloride channel (AgGluCl), and characterized its transcriptional patterns, protein expression and functional responses to glutamate and IVM. AgGluCl cloning revealed an unpredicted fourth splice isoform as well as a novel exon and splice site. The predicted gene products contained heterogeneity in the N-terminal extracellular domain and the intracellular loop region. Responses to glutamate and IVM were measured using two-electrode voltage clamp on Xenopus laevis oocytes expressing AgGluCl. IVM induced non-persistent currents in AgGluCl-a1 and did not potentiate glutamate responses. In contrast, AgGluCl-b was insensitive to IVM, suggesting that the AgGluCl gene could produce IVM-sensitive and -insensitive homomultimers from alternative splicing. AgGluCl isoformspecific transcripts were measured across tissues, ages, blood feeding status and sex, and were found to be differentially transcribed across these physiological variables. Lastly, we stained adult, female A. gambiae for GluCl expression. The channel was expressed in the antenna, Johnston's organ, supraesophageal ganglion and thoracic ganglia. In summary, we have characterized the first GluCl from a mosquito, A. gambiae, and described its unique activity and expression with respect to it as the target of the insecticide IVM.

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“…1), greatly exceeding 6 ng/ml, the concentration needed to kill 50% of Anopheles gambiae mosquitoes in 10 days (15). The two formulations showed similar pharmacokinetic patterns; formulation F eluted 47% of its ivermectin content, while formulation X eluted 55%.…”

mentioning

confidence: 99%

Pilot Study of a Slow-Release Ivermectin Formulation for Malaria Control in a Pig Model

Chaccour

Abizanda²,

Irigoyen

et al. 2017

Antimicrob Agents Chemother

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Vector control with long-lasting insecticidal nets (LLINs) and indoor residual spraying is responsible for more than two-thirds of the reduction in malaria prevalence seen in Africa over the last 15 years (1). Yet the behavioral plasticity of mosquito vectors can lead to residual transmission and possibly hamper elimination efforts (2, 3).One identified source of residual transmission is partial zoophagy. Mosquitoes that feed on peridomestic livestock can avoid contact with insecticides and survive to continue transmission once human blood is available again (3). This behavioral pattern could be seen after the scale-up of LLINs that put selective pressure on vectors that bite predominantly humans indoors (4), either by allowing a shift to a vector species with different behavior (5) or by selecting members of the same species that circumvent LLINs by biting outdoors (6) or outside sleeping hours (7).Ivermectin is an endectocide, a drug that kills ectoparasites that feed on the treated subjects. Ivermectin mass drug administration to humans has been proposed as a potential complementary measure to reduce malaria transmission (8). Additional treatment of peridomestic livestock with ivermectin could reduce malaria transmission by killing partially zoophagic vectors (9) and could also contribute to human well-being via the one-health concept, improving food production and economic benefits of animal owners (10).Ivermectin, however, has a relatively short half-life (3.5 days in pigs [11] and 2.8 days in cattle [12]), although veterinary use allows more flexibility in dose and route of administration. Even novel injectable formulations used at 3.15% in a 3-fold dose would sustain mosquito-killing concentrations for only a maximum estimated 40 days in cattle (13). Consideration should be given to longer-lasting formulations specifically conceived for vector control.We previously showed that subcutaneous long-lasting formulations sustained mosquitokilling ivermectin levels in a rabbit model for more than 6 months (14). Using the same formulations, we aimed at achieving stable and safe ivermectin levels in a larger mammal, the pig.We chose two 80-kg hybrid mini pigs to facilitate extrapolation to larger livestock such as cattle. We tested the two formulations of subcutaneous silicone rods that showed the most promising pharmacokinetic profile in our previous experiment (14). The rods are 40 mm in length and have a 1-mm radius; four or five devices are inserted subcutaneously in the back or thighs by means of a trocar used for commercially available hormonal implants. Formulation F contains 80% ivermectin (29 mg), 7% sucrose, and 13% deoxycholate. Formulation X contains 35% ivermectin (13 mg), 10% sucrose, and 55% deoxycholate, which greatly increases the elution of the drug (for further details on the implant design, refer to reference 14). Downloaded fromPlasma ivermectin levels were measured weekly for 12 weeks after the first month. At completion of the experiment, the implants were removed and the ivermectin remaini...

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Efficacy and Safety of the Mosquitocidal Drug Ivermectin to Prevent Malaria Transmission After Treatment: A Double-Blind, Randomized, Clinical Trial

Abstract: NCT0160325.

Cited by 105 publications

References 24 publications

Screening for an ivermectin slow-release formulation suitable for malaria vector control

Screening for an ivermectin slow-release formulation suitable for malaria vector control

Characterization of the target of ivermectin, the glutamate-gated chloride channel, fromAnopheles gambiae

Pilot Study of a Slow-Release Ivermectin Formulation for Malaria Control in a Pig Model

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