Implementation of an ivermectin-based community treatment strategy for the elimination of onchocerciasis or lymphatic filariasis has been delayed in Central Africa because of the occurrence of ...serious adverse events, including death, in persons with high levels of circulating Loa loa microfilariae. The LoaScope, a field-friendly diagnostic tool to quantify L. loa microfilariae in peripheral blood, enables rapid, point-of-care identification of persons at risk for serious adverse events.
A test-and-not-treat strategy was used in the approach to ivermectin treatment in the Okola health district in Cameroon, where the distribution of ivermectin was halted in 1999 after the occurrence of fatal events related to L. loa infection. The LoaScope was used to identify persons with an L. loa microfilarial density greater than 20,000 microfilariae per milliliter of blood, who were considered to be at risk for serious adverse events, and exclude them from ivermectin distribution. Active surveillance for posttreatment adverse events was performed daily for 6 days.
From August through October 2015, a total of 16,259 of 22,842 persons 5 years of age or older (71.2% of the target population) were tested for L. loa microfilaremia. Among the participants who underwent testing, a total of 15,522 (95.5%) received ivermectin, 340 (2.1%) were excluded from ivermectin distribution because of an L. loa microfilarial density above the risk threshold, and 397 (2.4%) were excluded because of pregnancy or illness. No serious adverse events were observed. Nonserious adverse events were recorded in 934 participants, most of whom (67.5%) had no detectable L. loa microfilariae.
The LoaScope-based test-and-not-treat strategy enabled the reimplementation of community-wide ivermectin distribution in a heretofore "off limits" health district in Cameroon and is a potentially practical approach to larger-scale ivermectin treatment for lymphatic filariasis and onchocerciasis in areas where L. loa infection is endemic. (Funded by the Bill and Melinda Gates Foundation and others.).
Scabies is an underrecognized cause of illness in many developing countries. It is associated with impetigo, which can lead to serious systemic complications. We conducted a trial of mass drug ...administration for scabies control in Fiji.
We randomly assigned three island communities to one of three different interventions for scabies control: standard care involving the administration of permethrin to affected persons and their contacts (standard-care group), mass administration of permethrin (permethrin group), or mass administration of ivermectin (ivermectin group). The primary outcome was the change in the prevalence of scabies and of impetigo from baseline to 12 months.
A total of 2051 participants were enrolled; 803 were in the standard-care group, 532 in the permethrin group, and 716 in the ivermectin group. From baseline to 12 months, the prevalence of scabies declined significantly in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 36.6% to 18.8% in the standard-care group (relative reduction in prevalence, 49%; 95% confidence interval CI, 37 to 60), from 41.7% to 15.8% in the permethrin group (relative reduction, 62%; 95% CI, 49 to 75), and from 32.1% to 1.9% in the ivermectin group (relative reduction, 94%; 95% CI, 83 to 100). The prevalence of impetigo also declined in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 21.4% to 14.6% in the standard-care group (relative reduction, 32%; 95% CI, 14 to 50), from 24.6% to 11.4% in the permethrin group (relative reduction, 54%; 95% CI, 35 to 73), and from 24.6% to 8.0% in the ivermectin group (relative reduction, 67%; 95% CI, 52 to 83). Adverse events were mild and were reported more frequently in the ivermectin group than in the permethrin group (15.6% vs. 6.8%).
Mass drug administration, particularly the administration of ivermectin, was efficacious for the control of scabies and impetigo. (Funded by the Australian National Health and Medical Research Council; Australian New Zealand Clinical Trials Registry number, ACTRN12613000474752.).
The macrocyclic lactones enjoy a position of prominence in the control of parasites, and their history may be of interest, and even of use, in an age in which the search for chemotherapeutic agents ...has been transformed by modern technology. Much of their history has been recorded piecemeal in a wide variety of publications. The present review provides additional detail, and offers a personal perspective on the history of ivermectin and related avermectins. Brief notes are included on the subsequent development of other macrocyclic lactones. Milbemycin preceded the avermectins as a macrocyclic lactone of agricultural importance, but was used for a different purpose. Development of the avermectins arose from the isolation, in the laboratories of the Kitasato Institute, of a novel soil-dwelling bacterium and its transmittal (in 1974) to the laboratories of Merck & Co., Inc. There it was found (in 1975) to produce a potent anthelmintic substance, which was then identified and transmuted by interdisciplinary research into an antiparasitic product. Initially the focus was on its applicability to veterinary science and animal husbandry; and after developmental research by many scientific teams, the product was introduced commercially (in 1981) for the control of endoparasitic nematodes and ectoparasitic arthropods in livestock. Subsequently, special applications in human medicine were developed, and were successfully implemented in partnership with World Health Organization and several non-governmental organizations (NGOs).
Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool ...to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms.
We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481.
Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 49% males and 1379 51% females; median age 15 years IQR 6–34), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 95% CI −0·79 to −0·21, p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events 3% among 1447 participants in the intervention group vs 24 events 2% among 1265 in the control group; risk ratio 1·63 1·01 to 2·67; risk difference 1·21 0·04 to 2·38, p=0·060), and no adverse reactions were reported.
Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace.
Bill & Melinda Gates Foundation.
Ivermectin is an FDA-approved broad-spectrum antiparasitic agent with demonstrated antiviral activity against a number of DNA and RNA viruses, including severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2). Despite this promise, the antiviral activity of ivermectin has not been consistently proven in vivo. While ivermectin's activity against SARS-CoV-2 is currently under investigation in patients, insufficient emphasis has been placed on formulation challenges. Here, we discuss challenges surrounding the use of ivermectin in the context of coronavirus disease-19 (COVID-19) and how novel formulations employing micro- and nanotechnologies may address these concerns.
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•Ivermectin is an FDA-approved antiparasitic agent, being currently investigated in COVID-19 patients•Ivermectin for COVID-19 is restrained by formulation challenges, whereas only oral dosage forms are available•The delivery of ivermectin by pulmonary route would provide high drug deposition in the airways and lungs•Expected efficacy by using aerosol micro- and nanocarriers containing ivermectin
Ivermectin – Old Drug, New Tricks? Laing, Roz; Gillan, Victoria; Devaney, Eileen
Trends in parasitology,
06/2017, Letnik:
33, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Ivermectin is one of the most important drugs in veterinary and human medicine for the control of parasitic infection and was the joint focus of the 2015 Nobel Prize in Physiology or Medicine, some ...35 years after its remarkable discovery. Although best described for its activity on glutamate-gated chloride channels in parasitic nematodes, understanding of its mode of action remains incomplete. In the field of veterinary medicine, resistance to ivermectin is now widespread, but the mechanisms underlying resistance are unresolved. Here we discuss the history of this versatile drug and its use in global health. Based on recent studies in a variety of systems, we question whether ivermectin could have additional modes of action on parasitic nematodes.
Glyphosate (GLY) is a widely used broad-spectrum herbicide, and ivermectin (IVM) is a commonly used antiparasitic in livestock farming. Both substances can be found in water bodies from agricultural ...areas and can have negative impacts on ecosystems. The aim of this study was to evaluate the lethal and sublethal toxicity individually and in combination of a glyphosate-based herbicide (GBH) and an ivermectin commercial formulation (ICF). Groups of 10 larvae were exposed for 504 h, in triplicate to a concentration gradient of the commercial formulation of glyphosate and ivermectin, individually, and to a series of dilutions of a non-equitoxic mixture of both compounds based on environmental concentrations. Additionally, biomarkers of oxidative stress (catalase, glutathione S-transferase, and reduced glutathione) and neurotoxicity (acetylcholinesterase and butyrylcholinesterase) were evaluated at sublethal and environmental concentrations of ivermectin (0.00125 mg/L) and glyphosate (0.7 mg/L) individually and in mixture. The ICF (LC50-504h: 0.047 mg ai IVM/L) was more toxic to larvae than the GBH (LC50-504h: 24.73 mg ae GLY/L). In terms of lethality, exposure to the mixture was synergistic at all exposure times. Both compounds separately caused alterations in the biomarkers of oxidative stress and neurotoxicity. Regarding sublethal effects in organisms exposed to the mixture, potentiation was observed in acetylcholinesterase. The simultaneous exposure to both substances in water bodies can have synergistic and negative effects on aquatic organisms.
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•Joint and single toxicity of glyphosate (GLY) and ivermectin (IVM) was assessed.•IVM was more toxic than GLY and the mixture lethal toxicity was synergistic.•GLY and IVM altered biomarkers of oxidative stress and neurotoxicity.•A potentiation effect was observed for the neurotoxicity biomarker in the mixture.•Joint exposure to GLY and IVM in water bodies may result in synergistic effects.
Scabies is an intensely itchy parasitic infection of the skin. It occurs worldwide, but is particularly problematic in areas of poor sanitation, overcrowding, and social disruption. In recent years, ...permethrin and ivermectin have become the most relevant treatment options for scabies.
To assess the efficacy and safety of topical permethrin and topical or systemic ivermectin for scabies in people of all ages.
We searched the following databases up to 25 April 2017: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and IndMED. We searched the World Health Organization International Clinical Trials Registry Platform, the ISRCTN registry, CenterWatch Clinical Trials Listing, ClinicalTrials.gov, TrialsCentral, and the UK Department of Health National Research Register for ongoing trials. We also searched multiple sources for grey literature and checked reference lists of included studies for additional trials.
We included randomized controlled trials that compared permethrin or ivermectin against each other for people with scabies of all ages and either sex.
Two review authors independently screened the identified records, extracted data, and assessed the risk of bias for the included trials.The primary outcome was complete clearance of scabies. Secondary outcomes were number of participants re-treated, number of participants with at least one adverse event, and number of participants withdrawn from study due to an adverse event.We summarized dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). If it was not possible to calculate the point estimate, we described the data qualitatively. Where appropriate, we calculated combined effect estimates using a random-effects model and assessed heterogeneity. We calculated numbers needed to treat for an additional beneficial outcome when we found a difference.We assessed the certainty of the evidence using the GRADE approach. We used the control rate average to provide illustrative clearance rates in the comparison groups.
Fifteen studies (1896 participants) comparing topical permethrin, systemic ivermectin, or topical ivermectin met the inclusion criteria. Overall, the risk of bias in the included trials was moderate: reporting in many studies was poor. Nearly all studies were conducted in South Asia or North Africa, where the disease is more common, and is associated with poverty.EfficacyOral ivermectin (at a standard dose of 200 μg/kg) may lead to slightly lower rates of complete clearance after one week compared to permethrin 5% cream. Using the average clearance rate of 65% in the trials with permethrin, the illustrative clearance with ivermectin is 43% (RR 0.65, 95% CI 0.54 to 0.78; 613 participants, 6 studies; low-certainty evidence). However, by week two there may be little or no difference (illustrative clearance of permethrin 74% compared to ivermectin 68%; RR 0.91, 95% CI 0.76 to 1.08; 459 participants, 5 studies; low-certainty evidence). Treatments with one to three doses of ivermectin or one to three applications of permethrin may lead to little or no difference in rates of complete clearance after four weeks' follow-up (illustrative cures with 1 to 3 applications of permethrin 93% and with 1 to 3 doses of ivermectin 86%; RR 0.92, 95% CI 0.82 to 1.03; 581 participants, 5 studies; low-certainty evidence).After one week of treatment with oral ivermectin at a standard dose of 200 μg/kg or one application of permethrin 5% lotion, there is probably little or no difference in complete clearance rates (illustrative cure rates: permethrin 73%, ivermectin 68%; RR 0.93, 95% CI 0.74 to 1.17; 120 participants, 1 study; moderate-certainty evidence). After two weeks of treatment, one dose of systemic ivermectin compared to one application of permethrin lotion may lead to similar complete clearance rates (extrapolated cure rates: 67% in both groups; RR 1.00, 95% CI 0.78 to 1.29; 120 participants, 1 study; low-certainty evidence).There is probably little or no difference in rates of complete clearance between systemic ivermectin at standard dose and topical ivermectin 1% lotion four weeks after initiation of treatment (illustrative cure rates: oral ivermectin 97%, ivermectin lotion 96%; RR 0.99, 95% CI 0.95 to 1.03; 272 participants, 2 studies; moderate-certainty evidence). Likewise, after four weeks, ivermectin lotion probably leads to little or no difference in rates of complete clearance when compared to permethrin cream (extrapolated cure rates: permethrin cream 94%, ivermectin lotion 96%; RR 1.02, 95% CI 0.96 to 1.08; 210 participants, 1 study; moderate-certainty evidence), and there is little or no difference among systemic ivermectin in different doses (extrapolated cure rates: 2 doses 90%, 1 dose 87%; RR 0.97, 95% CI 0.83 to 1.14; 80 participants, 1 study; high-certainty evidence).SafetyReporting of adverse events in the included studies was suboptimal. No withdrawals due to adverse events occurred in either the systemic ivermectin or the permethrin group (moderate-certainty evidence). Two weeks after treatment initiation, there is probably little or no difference in the proportion of participants treated with systemic ivermectin or permethrin cream who experienced at least one adverse event (55 participants, 1 study; moderate-certainty evidence). After four weeks, ivermectin may lead to a slightly larger proportion of participants with at least one adverse event (extrapolated rates: permethrin 4%, ivermectin 5%; RR 1.30, 95% CI 0.35 to 4.83; 502 participants, 4 studies; low-certainty evidence).Adverse events in participants treated with topical ivermectin were rare and of mild intensity and comparable to those with systemic ivermectin. For this comparison, it is uncertain whether there is any difference in the number of participants with at least one adverse event (very low-certainty evidence). No withdrawals due to adverse events occurred (62 participants, 1 study; moderate-certainty evidence).It is uncertain whether topical ivermectin or permethrin differ in the number of participants with at least one adverse event (very low-certainty evidence). We found no studies comparing systemic ivermectin in different doses that assessed safety outcomes.
We found that for the most part, there was no difference detected in the efficacy of permethrin compared to systemic or topical ivermectin. Overall, few and mild adverse events were reported. Our confidence in the effect estimates was mostly low to moderate. Poor reporting is a major limitation.
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