94 research outputs found
Ivermectin to reduce malaria transmission II. Considerations regarding clinical development pathway
The 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
Vector 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
Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety
Ivermectin 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.
As 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
Ivermectin 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.
Ivermectin 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
Mapping the potential use of endectocide-treated cattle to reduce malaria transmission
Treating cattle with endectocide is a longstanding
veterinary practice to reduce the load of endo and
ectoparasites, but has the potential to be added to the malaria
control and elimination toolbox, as it also kills malaria
mosquitoes feeding on the animals. Here we used openly available
data to map the areas of the African continent where high
malaria prevalence in 2-10 year old children coincides with a
high density of cattle and high density of the partly zoophilic
malaria vector Anopheles arabiensis. That is, mapping the areas
where treating cattle with endectocide would potentially have
the greatest impact on reducing malaria transmission. In regions
of Africa that are not dominated by rainforest nor desert, the
map shows a scatter of areas in several countries where this
intervention shows potential, including central and eastern
sub-Saharan Africa. The savanna region underneath the Sahel in
West Africa appears as the climatic block that would benefit to
the largest extent from this intervention, encompassing several
countries. West Africa currently presents the highest under-10
malaria prevalence and elimination within the next twenty years
cannot be contemplated there with currently available
interventions alone, making the use of endectocide treated
cattle as a complementary intervention highly appealing
Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study.
BACKGROUND
Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively.
METHODS
We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification.
RESULTS
Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin.
CONCLUSION
There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin
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