111 research outputs found
Advancing the repurposing of ivermectin for malaria
Get PDFThere is ever-increasing anticipation for the potential of mass drug administration of endectocides (also known as systemic insecticides) to reduce malaria transmission, with ivermectin emerging as the most likely first-in-class endectocide.1 More than half of the 46 papers published on this subject in the past decade appeared in the past 2 years. 23 projects are registered in the MESA Track database, of which seven are active today; and, more importantly, trial mapping by the Malaria Ivermectin Roadmap2 shows that abundant new evidence on the topic will be available by 2020
Ivermectin to reduce malaria transmission II. Considerations regarding clinical development pathway
Get PDFThe development of ivermectin as a complementary vector control
tool will require good quality evidence. This paper reviews the
different eco-epidemiological contexts in which mass drug
administration with ivermectin could be useful. Potential
scenarios and pharmacological strategies are compared in order
to help guide trial design. The rationale for a particular
timing of an ivermectin-based tool and some potentially useful
outcome measures are suggested
Ivermectin to reduce malaria transmission III. Considerations regarding regulatory and policy pathways
Get PDFVector control is a task previously relegated to products that
(a) kill the mosquitoes directly at different stages
(insecticides, larvicides, baited traps), or (b) avoid/reduce
human-mosquito contact (bed nets, repellents, house screening),
thereby reducing transmission. The potential community-based
administration of the endectocide ivermectin with the intent to
kill mosquitoes that bite humans, and thus reduce malaria
transmission, offers a novel approach using a well-known drug,
but additional steps are required to address technical,
regulatory and policy gaps. The proposed community
administration of this drug presents dual novel paradigms;
first, indirect impact on the community rather than on
individuals, and second, the use of a drug for vector control.
In this paper, the main questions related to the regulatory and
policy pathways for such an application are identified. Succinct
answers are proposed for how the efficacy, safety,
acceptability, cost-effectiveness and programmatic suitability
could result in regulatory approval and ultimately policy
recommendations on the use of ivermectin as a complementary
vector control tool
Mind the gap: residual malaria transmission, veterinary endectocides and livestock as targets for malaria vector control
Get PDFIvermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety
Get PDFIvermectin is an endectocide that has been used broadly in
single dose community campaigns for the control of
onchocerciasis and lymphatic filariasis for more than 30 years.
There is now interest in the potential use of ivermectin
regimens to reduce malaria transmission, envisaged as
community-wide campaigns tailored to transmission patterns and
as complement of the local vector control programme. The
development of new ivermectin regimens or other novel
endectocides will require integrated development of the drug in
the context of traditional entomological tools and endpoints.
This document examines the main pharmacokinetic and
pharmacodynamic parameters of the medicine and their potential
influence on its vector control efficacy and safety at
population level. This information could be valuable for trial
design and clinical development into regulatory and policy
pathways
Effectiveness of Antiviral Therapy in Highly-Transmissible Variants of SARS-CoV-2: A Modeling and Simulation Study.
Get PDFAs of October 2021, neither established agents (e.g., hydroxychloroquine) nor experimental drugs have lived up to their initial promise as antiviral treatment against SARS-CoV-2 infection. While vaccines are being globally deployed, variants of concern (VOCs) are emerging with the potential for vaccine escape. VOCs are characterized by a higher within-host transmissibility, and this may alter their susceptibility to antiviral treatment. Here we describe a model to understand the effect of changes in within-host reproduction number R0, as proxy for transmissibility, of VOCs on the effectiveness of antiviral therapy with molnupiravir through modeling and simulation. Molnupiravir (EIDD-2801 or MK 4482) is an orally bioavailable antiviral drug inhibiting viral replication through lethal mutagenesis, ultimately leading to viral extinction. We simulated 800 mg molnupiravir treatment every 12 h for 5 days, with treatment initiated at different time points before and after infection. Modeled viral mutations range from 1.25 to 2-fold greater transmissibility than wild type, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Total viral load was reduced by up to 70% in highly transmissible variants compared to 30% in wild type if treatment was started in the first 1-3 days post inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible SARS-CoV-2 variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis
Advancing the repurposing of ivermectin for malaria
Get PDFIvermectin lays the path for a whole new concept: drug-based vector control. Ivermectin, or indeed any effective endectocide, could be administered to eligible members of the at-risk community as a complementary tool for vector control. It could be administered alone or in combination with partner drugs to allow for integrated management of malaria or neglected tropical diseases, directly responding to residual transmission by targeting malaria and some lymphatic filariasis vectors, regardless of their feeding behaviour
Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency.
Get PDFIvermectin is a widely used drug for the treatment and control of several neglected tropical diseases.The drug has an excellent safety profile, with more than 2.5 billion doses distributed in the last 30 years, and its potential to reduce malaria transmission by killing mosquitoes is under evaluation in several trials around the
world. Ivermectin inhibits the in vitro replication of some positive, single-stranded RNA viruses, namely, dengue virus (DNV), Zika virus, yellow fever virus, and others
Ivermectin resistance mechanisms in ectoparasites: a scoping review
Get PDFIvermectin mass drug administration has been used for decades to target human and veterinary ectoparasites, and is currently being considered for use against malaria vectors. Although there have been few reports of resistance to date in human ectoparasites, we must anticipate the development of resistance in mosquitoes in the future. Hence, through this review, we mapped the existing evidence on ivermectin resistance mechanisms in human ectoparasites. A search was conducted on the 8th November 2023 through databases, PubMed, Web of Science, and Google Scholar, using terms related to ivermectin, human and veterinary ectoparasites, and resistance. Abstracts (5893) were screened by JFA and CK. Data on the study organism, the type of resistance, the analysis methods, and, where applicable, the gene loci of interest were extracted from the studies. Details of the methodology and results of each study were summarised narratively and in a table. Eighteen studies were identified describing ivermectin resistance in ectoparasites. Two studies described target site resistance; and 16 studies reported metabolic resistance and/or changes in efflux pump expression. The studies investigated genetic mutations in resistant organisms, detoxification, and efflux pump expression in resistant versus susceptible organisms, and the effect of synergists on mortality or detoxification enzyme/efflux pump transcription. To date, very few studies have been conducted examining the mechanisms of ivermectin resistance in ectoparasites, with only two on Anopheles spp. Of the existing studies, most examined detoxification and efflux pump gene expression, and only two studies in lice investigated target-site resistance. Further research in this field should be encouraged, to allow for close monitoring in ivermectin MDA programmes, and the development of resistance mitigation strategies. Graphical Abstract
Effects of larval exposure to sublethal doses of ivermectin on adult fitness and susceptibility to ivermectin in Anopheles gambiae s.s.
Get PDFBackground: The effects of ivermectin (endectocide) on mosquito survival make it a potential new malaria vector control tool. The drug can be administered to mosquito disease vectors through blood hosts that include humans and livestock. Its increased use may cause contamination of larval habitats, either directly through livestock excreta or indirectly through leaching or run-off from contaminated soil, albeit in sublethal doses. However, the effects of such exposure on immature stages and the subsequent adults that emerge are poorly understood. This study was undertaken to evaluate the impact of ivermectin exposure on Anopheles gambiae s.s. larvae and its effects on fitness and susceptibility to ivermectin in the emerging adults.
Methods: Laboratory-reared An. gambiae s.s. (Kilifi strain) larvae were exposed to five different ivermectin concentrations; 0, 0.00001, 0.0001, 0.001, and 0.01 ppm, and larval survival was monitored to determine the appropriate sub-lethal dose. Concentrations with survival > 50% (0.00001 and 0.0001 ppm) were selected and used as the sub-lethal doses. The fecundity, fertility, and susceptibility to ivermectin of adults emerging after larval exposure to the sub-lethal doses were examined.
Results: Overall, exposure of An. gambiae s.s. aquatic stages to ivermectin caused a dose-dependent reduction in larval survival irrespective of the stage at which the larvae were exposed. Exposure to ivermectin in the larval stage did not have an effect on either the number of eggs laid or the hatch rate. However, exposure of first/second-instar larvae to 0.0001 ppm and third/fourth-instar larvae to 0.001 ppm of ivermectin reduced the time taken to oviposition. Additionally, exposure to ivermectin in the larval stage did not affect susceptibility of the emerging adults to the drug.
Conclusions: This study shows that contamination of larval habitats with ivermectin affects An. gambiae s.s. larval survival and could potentially have an impact on public health. However, there are no carry-over effects on the fecundity, fertility, and susceptibility of the emerging adults to ivermectin. In addition, this study shows that environmental exposure to ivermectin in the larval habitats is unlikely to compromise the efficacy of ivermectin in the emerging adults
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