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Toxicology Reports 2016As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between...
As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants and gene expression. In the present study, a novel "aggregating bundles of clusters" (ABC) procedure was applied to separate cholestatic from non-cholestatic drugs and model toxicants in the Johnson & Johnson (Janssen) rat liver toxicogenomics database [3]. Drug-induced cholestasis is an important issue, particularly when a new compound enters the market with this liability, with standard preclinical models often mispredicting this toxicity. Three well-characterized cholestasis-responsive genes (Cyp7a1, Mrp3 and Bsep) were chosen from a previous in-house Janssen gene expression signature; these three genes show differing, non-redundant responses across the 90+ paradigm compounds in our database. Using the ABC procedure, extraneous contributions were minimized in comparisons of compound gene responses. All genes were assigned weights proportional to their correlations with Cyp7a1, Mrp3 and Bsep, and a resampling technique was used to derive a stable measure of compound similarity. The compounds that were known to be associated with rat cholestasis generally had small values of this measure relative to each other but also had large values of this measure relative to non-cholestatic compounds. Visualization of the data with the ABC-derived signature showed a very tight, essentially identically behaving cluster of robust human cholestatic drugs and experimental cholestatic toxicants (ethinyl estradiol, LPS, ANIT and methylene dianiline, disulfiram, naltrexone, methapyrilene, phenacetin, alpha-methyl dopa, flutamide, the NSAIDs--indomethacin, flurbiprofen, diclofenac, flufenamic acid, sulindac, and nimesulide, butylated hydroxytoluene, piperonyl butoxide, and bromobenzene), some slightly less active compounds (3'-acetamidofluorene, amsacrine, hydralazine, tannic acid), some drugs that behaved very differently, and were distinct from both non-cholestatic and cholestatic drugs (ketoconazole, dipyridamole, cyproheptadine and aniline), and many postulated human cholestatic drugs that in rat showed no evidence of cholestasis (chlorpromazine, erythromycin, niacin, captopril, dapsone, rifampicin, glibenclamide, simvastatin, furosemide, tamoxifen, and sulfamethoxazole). Most of these latter drugs were noted previously by other groups as showing cholestasis only in humans. The results of this work suggest that the ABC procedure and similar statistical approaches can be instrumental in combining data to compare toxicants across toxicogenomics databases, extract similarities among responses and reduce unexplained data varation.
PubMed: 28959545
DOI: 10.1016/j.toxrep.2016.01.009 -
Frontiers in Physiology 2020(Koch) is an economically important pest that affects legumes in worldwide. Chemical control is still the primary efficient method for management. However, the...
(Koch) is an economically important pest that affects legumes in worldwide. Chemical control is still the primary efficient method for management. However, the mechanism underlying insecticide resistance in has not been elucidated. A previous study observed that piperonyl butoxide (PBO) and diethyl maleate (DEM) significantly synergized imidacloprid in field populations, indicating that cytochrome P450 (P450) and glutathione S-transferase (GST) genes may play pivotal roles in imidacloprid resistance. In this study, 38 P450 genes and 10 GST genes were identified in through transcriptomic analysis. The expression levels of these P450 and GST genes were measured in susceptible (SUS) strains of under imidacloprid treatment with LC, LC, and LC doses. The expression levels of , , , , , , and were up-regulated in the three treatments. Most of these genes belong to CYP3 and CYP4 Clans. In addition, the expression levels of all P450 and GST genes in were also measured in the Juye (JY) and Linqing (LQ) field populations. The expression levels of , , and were up-regulated in the SUS strain after imidacloprid treatment at three doses, and these genes were overexpressed in the JY population. Furthermore, the sensitivity of to imidacloprid was significantly increased after knockdown of and through RNA interference. These results may help to elucidate the mechanisms underlying of imidacloprid resistance in .
PubMed: 33551847
DOI: 10.3389/fphys.2020.624287 -
The Lancet. Planetary Health Feb 2022Concern that insecticide resistant mosquitoes are threatening malaria control has driven the development of new types of insecticide treated nets (ITNs) and indoor...
BACKGROUND
Concern that insecticide resistant mosquitoes are threatening malaria control has driven the development of new types of insecticide treated nets (ITNs) and indoor residual spraying (IRS) of insecticide. Malaria control programmes have a choice of vector control interventions although it is unclear which controls should be used to combat the disease. The study aimed at producing a framework to easily compare the public health impact and cost-effectiveness of different malaria prevention measures currently in widespread use.
METHODS
We used published data from experimental hut trials conducted across Africa to characterise the entomological effect of pyrethroid-only ITNs versus ITNs combining a pyrethroid insecticide with the synergist piperonyl butoxide (PBO). We use these estimates to parameterise a dynamic mathematical model of Plasmodium falciparum malaria which is validated for two sites by comparing simulated results to empirical data from randomised control trials (RCTs) in Tanzania and Uganda. We extrapolated model simulations for a series of potential scenarios likely across the sub-Saharan African region and include results in an online tool (Malaria INtervention Tool [MINT]) that aims to identify optimum vector control intervention packages for scenarios with varying budget, price, entomological and epidemiological factors.
FINDINGS
Our model indicates that switching from pyrethroid-only to pyrethroid-PBO ITNs could averted up to twice as many cases, although the additional benefit is highly variable and depends on the setting conditions. We project that annual delivery of long-lasting, non-pyrethroid IRS would prevent substantially more cases over 3-years, while pyrethroid-PBO ITNs tend to be the most cost-effective intervention per case averted. The model was able to predict prevalence and efficacy against prevalence in both RCTs for the intervention types tested. MINT is applicable to regions of sub-Saharan Africa with endemic malaria and provides users with a method of designing intervention packages given their setting and budget.
INTERPRETATION
The most cost-effective vector control package will vary locally. Models able to recreate results of RCTs can be used to extrapolate outcomes elsewhere to support evidence-based decision making for investment in vector control.
FUNDING
Medical Research Council, IVCC, Wellcome Trust.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Animals; Insecticide-Treated Bednets; Malaria; Mosquito Control; Piperonyl Butoxide; Tanzania
PubMed: 35065707
DOI: 10.1016/S2542-5196(21)00296-5 -
Scientific Reports Apr 2022Pirimiphos-methyl is a pro-insecticide requiring activation by mosquito cytochrome P450 enzymes to induce toxicity while PBO blocks activation of these enzymes in...
Pirimiphos-methyl is a pro-insecticide requiring activation by mosquito cytochrome P450 enzymes to induce toxicity while PBO blocks activation of these enzymes in pyrethroid-resistant vector mosquitoes. PBO may thus antagonise the toxicity of pirimiphos-methyl IRS when combined with pyrethroid-PBO ITNs. The impact of combining Olyset Plus and PermaNet 3.0 with Actellic 300CS IRS was evaluated against pyrethroid-resistant Anopheles gambiae s.l. in two parallel experimental hut trials in southern Benin. The vector population was resistant to pyrethroids and PBO pre-exposure partially restored deltamethrin toxicity but not permethrin. Mosquito mortality in experimental huts was significantly improved in the combinations of bendiocarb IRS with pyrethroid-PBO ITNs (33-38%) compared to bendiocarb IRS alone (14-16%, p < 0.001), demonstrating an additive effect. Conversely, mortality was significantly reduced in the combinations of pirimiphos-methyl IRS with pyrethroid-PBO ITNs (55-59%) compared to pirimiphos-methyl IRS alone (77-78%, p < 0.001), demonstrating evidence of an antagonistic effect when both interventions are applied in the same household. Mosquito mortality in the combination was significantly higher compared to the pyrethroid-PBO ITNs alone (55-59% vs. 22-26% p < 0.001) showing potential of pirimiphos-methyl IRS to enhance vector control when deployed to complement pyrethroid-PBO ITNs in an area where PBO fails to fully restore susceptibility to pyrethroids.
Topics: Animals; Anopheles; Insecticide Resistance; Malaria; Mosquito Control; Mosquito Vectors; Organothiophosphorus Compounds; Piperonyl Butoxide; Pyrethrins
PubMed: 35478216
DOI: 10.1038/s41598-022-10953-y -
Journal of Medical Entomology Nov 2020The impact of increasing resistance of mosquitoes to conventional pesticides has led to investigate various unique tools and pest control strategies. Herein, we assessed...
The impact of increasing resistance of mosquitoes to conventional pesticides has led to investigate various unique tools and pest control strategies. Herein, we assessed the potency of flupyradifurone, a novel pesticide, on fourth instar larvae of Culex quinquefasciatus Say. Further, we evaluated the synergistic action of piperonyl butoxide (PBO) and the octopamine receptor agonists (OR agonists) chlordimeform (CDM) and amitraz (AMZ) on the toxicity of flupyradifurone in comparison with sulfoxaflor and nitenpyram to increase their toxicity on Cx. quinquefasciatus. Results demonstrated that flupyradifurone was the most potent pesticide followed by sulfoxaflor and nitenpyram. Further, the synergetic effect of PBO, CDM, and AMZ was significant for all selected pesticides especially flupyradifurone. However, AMZ had the most significant effect in combination with the selected pesticides followed by CDM and PBO. The toxicity of the pesticides was time-dependent and increased over time from 24, 48, to 72 h of exposure in all experiments. The results indicate that flupyradifurone is a promising component in future mosquito control programs.
Topics: 4-Butyrolactone; Animals; Chlorphenamidine; Culex; Insect Proteins; Insecticides; Larva; Mosquito Control; Neonicotinoids; Piperonyl Butoxide; Pyridines; Receptors, Biogenic Amine; Sulfur Compounds; Toluidines
PubMed: 32566941
DOI: 10.1093/jme/tjaa118 -
The Lancet. Infectious Diseases Jan 2024New classes of long-lasting insecticidal nets (LLINs) containing two active ingredients have been recently recommended by WHO in areas where malaria vectors are... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of long-lasting insecticidal nets with pyriproxyfen-pyrethroid, chlorfenapyr-pyrethroid, or piperonyl butoxide-pyrethroid versus pyrethroid only against malaria in Tanzania: final-year results of a four-arm, single-blind, cluster-randomised trial.
BACKGROUND
New classes of long-lasting insecticidal nets (LLINs) containing two active ingredients have been recently recommended by WHO in areas where malaria vectors are resistant to pyrethroids. This policy was based on evidence generated by the first 2 years of our recently published trial in Tanzania. In this Article, we report the final third-year trial findings, which are necessary for assessing the long-term effectiveness of new classes of LLIN in the community and the replacement intervals required.
METHODS
A third year of follow-up of a four-arm, single-blind, cluster-randomised controlled trial of dual active ingredient LLINs was conducted between July 14, 2021, and Feb 10, 2022, in Misungwi, Tanzania. Restricted randomisation was used to assign 84 clusters to the four LLIN groups (1:1:1:1) to receive either standard pyrethroid (PY) LLINs (reference), chlorfenapyr-PY LLINs, pyriproxyfen-PY LLINs, or piperonyl butoxide (PBO)-PY LLINs. All households received one LLIN for every two people. Data collection was done in consenting households in the cluster core area with at least one child between 6 months and 15 years of age who permanently resided in the selected household. Exclusion criteria were householders absent during the visit, living in the cluster buffer area, no adult caregiver capable of giving informed consent, or eligible children who were severely ill. Field staff and study participants were masked to allocation, and those analysing data were not. The primary 24-month endpoint was reported previously; here, we present the secondary outcome, malaria infection prevalence in children at 36 months post LLIN distribution, reported in the intention-to-treat analysis. The trial was registered with ClinicalTrials.gov (NCT03554616) and is now complete.
FINDINGS
Overall usage of study nets was 1023 (22·3%) of 4587 people at 36 months post distribution. In the standard PY LLIN group, malaria infection was prevalent in 407 (37·4%) of 1088 participants, compared with 261 (22·8%) of 1145 in the chlorfenapyr-PY LLIN group (odds ratio 0·57, 95% CI 0·38-0·86; p=0·0069), 338 (32·2%) of 1048 in the PBO-PY LLIN group (0·95, 0·64-1·42; p=0·80), and 302 (28·8%) of 1050 in the pyriproxyfen-PY LLIN group (0·82, 0·55-1·23; p=0·34). None of the participants or caregivers reported side-effects.
INTERPRETATION
Despite low coverage, the protective efficacy against malaria offered by chlorfenapyr-PY LLINs was superior to that provided by standard PY LLINs over a 3-year LLIN lifespan. Appropriate LLIN replacement strategies to maintain adequate usage of nets will be necessary to maximise the full potential of these nets.
FUNDING
Department for International Development, UK Medical Research Council, Wellcome Trust, Department of Health and Social Care, and Bill & Melinda Gates Foundation via the Innovative Vector Control Consortium.
Topics: Child; Humans; Insecticides; Piperonyl Butoxide; Tanzania; Single-Blind Method; Insecticide Resistance; Insecticide-Treated Bednets; Pyrethrins; Malaria; Mosquito Control
PubMed: 37776879
DOI: 10.1016/S1473-3099(23)00420-6 -
Current Research in Parasitology &... 2023Insecticide resistance threatens recent progress on malaria control in Africa. To characterize pyrethroid resistance in Uganda, (.) and were analyzed from 11 sites...
Insecticide resistance threatens recent progress on malaria control in Africa. To characterize pyrethroid resistance in Uganda, (.) and were analyzed from 11 sites with varied vector control strategies. Mosquito larvae were collected between May 2018 and December 2020. Sites were categorized as receiving no indoor-residual spraying ('no IRS', = 3); where IRS was delivered from 2009 to 2014 and in 2017 and then discontinued ('IRS stopped', = 4); and where IRS had been sustained since 2014 ('IRS active', = 4). IRS included bendiocarb, pirimiphos methyl and clothianidin. All sites received long-lasting insecticidal nets (LLINs) in 2017. Adult mosquitoes were exposed to pyrethroids; with or without piperonyl butoxide (PBO). (.) and were identified using PCR. (.) were genotyped for /, , , , and , while were examined for /. Overall, 2753 (.), including 1105 (.) and 1648 were evaluated Species composition varied by site; only nine (.) were collected from 'IRS active' sites, precluding species-specific comparisons. Overall, mortality following exposure to permethrin and deltamethrin was 18.8% (148/788) in (.) and 74.6% (912/1222) in . Mortality was significantly lower in (.) than in in 'no IRS' sites (permethrin: 16.1 67.7%, < 0.001; deltamethrin: 24.6 83.7%, < 0.001) and in 'IRS stopped' sites (permethrin: 11.3 63.6%, < 0.001; deltamethrin: 25.6 88.9%, < 0.001). When PBO was added, mortality increased for (.) and . Most (.) had the mutation (95% frequency) and the resistance allele (87%), while the frequency of and were lower (52% and 55%, respectively). Resistance to pyrethroids was widespread and higher in (.). Where IRS was active, dominated. Addition of PBO to pyrethroids increased mortality, supporting deployment of PBO LLINs. Further surveillance of insecticide resistance and assessment of associations between genotypic markers and phenotypic outcomes are needed to better understand mechanisms of pyrethroid resistance and to guide vector control.
PubMed: 36590346
DOI: 10.1016/j.crpvbd.2022.100106 -
Infectious Diseases of Poverty Aug 2023The increasing reports of resistance to pyrethroid insecticides associated with reduced efficacy of pyrethroid-only interventions highlight the urgency of introducing...
BACKGROUND
The increasing reports of resistance to pyrethroid insecticides associated with reduced efficacy of pyrethroid-only interventions highlight the urgency of introducing new non-pyrethroid-only control tools. Here, we investigated the performance of piperonyl-butoxide (PBO)-pyrethroid [Permanet 3.0 (P3.0)] and dual active ingredients (AI) nets [Interceptor G2 (IG2): containing pyrethroids and chlorfenapyr and Royal Guard (RG): containing pyrethroids and pyriproxyfen] compared to pyrethroid-only net Royal Sentry (RS) against pyrethroid-resistant malaria vectors in Cameroon.
METHODS
The efficacy of these tools was firstly evaluated on Anopheles gambiae s.l. and Anopheles funestus s.l. from Gounougou, Mibellon, Mangoum, Nkolondom, and Elende using cone/tunnel assays. In addition, experimental hut trials (EHT) were performed to evaluate the performance of unwashed and 20 times washed nets in semi-field conditions. Furthermore, pyrethroid-resistant markers were genotyped in dead vs alive, blood-fed vs unfed mosquitoes after exposure to the nets to evaluate the impact of these markers on net performance. The XLSTAT software was used to calculate the various entomological outcomes and the Chi-square test was used to compare the efficacy of various nets. The odds ratio and Fisher exact test were then used to establish the statistical significance of any association between insecticide resistance markers and bed net efficacy.
RESULTS
Interceptor G2 was the most effective net against wild pyrethroid-resistant An. funestus followed by Permanet 3.0. In EHT, this net induced up to 87.8% mortality [95% confidence interval (CI): 83.5-92.1%) and 55.6% (95% CI: 48.5-62.7%) after 20 washes whilst unwashed pyrethroid-only net (Royal Sentry) killed just 18.2% (95% CI: 13.4-22.9%) of host-seeking An. funestus. The unwashed Permanet 3.0 killed up to 53.8% (95% CI: 44.3-63.4%) of field-resistant mosquitoes and 47.2% (95% CI: 37.7-56.7%) when washed 20 times, and the Royal Guard 13.2% (95% CI: 9.0-17.3%) for unwashed net and 8.5% (95% CI: 5.7-11.4%) for the 20 washed net. Interceptor G2, Permanet 3.0, and Royal Guard provided better personal protection (blood-feeding inhibition 66.2%, 77.8%, and 92.8%, respectively) compared to pyrethroid-only net Royal Sentry (8.4%). Interestingly, a negative association was found between kdrw and the chlorfenapyr-based net Interceptor G2 (χ = 138; P < 0.0001) with homozygote-resistant mosquitoes predominantly found in the dead ones.
CONCLUSIONS
The high mortality recorded with Interceptor G2 against pyrethroid-resistant malaria vectors in this study provides first semi-field evidence of high efficacy against these major malaria vectors in Cameroon encouraging the implementation of this novel net for malaria control in the country. However, the performance of this net should be established in other locations and on other major malaria vectors before implementation at a large scale.
Topics: Animals; Cameroon; Anopheles; Malaria; Mosquito Vectors
PubMed: 37641108
DOI: 10.1186/s40249-023-01132-w -
Lancet (London, England) Mar 2022Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness and cost-effectiveness against malaria of three types of dual-active-ingredient long-lasting insecticidal nets (LLINs) compared with pyrethroid-only LLINs in Tanzania: a four-arm, cluster-randomised trial.
BACKGROUND
Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors. We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors.
METHODS
We did a four-arm, cluster-randomised trial in Misungwi, Tanzania. Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area. Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group). At least one LLIN was distributed for every two people. Community members and the field team were masked to group allocation. Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests. The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population. The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups. This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting.
FINDINGS
84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018. 147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019. Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups. Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54-1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67-1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30-0·67], p=0·0001). Skin irritation or paraesthesia was the most commonly reported side-effect in all groups. Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1-105) more to public providers or $28 (11-120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives.
INTERPRETATION
After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292-393 per DALY averted). Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness. Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs.
FUNDING
Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative.
Topics: Animals; Child; Cost-Benefit Analysis; Cross-Sectional Studies; Humans; Insecticide-Treated Bednets; Insecticides; Malaria; Mosquito Control; Pyrethrins; Tanzania
PubMed: 35339225
DOI: 10.1016/S0140-6736(21)02499-5 -
The Journal of Toxicological Sciences 2012The present study examined hepatic estrogen receptor (ER) and androgen receptor (AR) levels as well as estrogen-signaling status in a model of rat hepatic hypertrophy...
The present study examined hepatic estrogen receptor (ER) and androgen receptor (AR) levels as well as estrogen-signaling status in a model of rat hepatic hypertrophy induced by phenobarbital (PB), chlofibrate (CF), or piperonyl butoxide (PBO). Male F344 rats were fed with PB at 2,500 ppm, CF at 2,500 ppm, and PBO at 20,000 ppm for 3 days, 4 weeks, and 13 weeks. CF and PBO induced diffuse hypertrophy, while centrilobular hypertrophy was observed with PB administration. The levels of mRNA for ERα, AR and leukemia inhibitory factor receptor (LIFR) which was found to be estrogen responsive in the present study, were determined by quantitative RT-PCR. In the CF and PBO groups, ERα mRNA expression was reduced, and consequently, the expression of a responsive gene, LIFR, was also decreased, while PB had no effect on ER mRNA levels. AR mRNA expression decreased in all the treated groups, but reduction was persistent only in PB group. Recently, LIFR was identified as a tumor suppressor gene in human HCC. Thus, LIFR may be one of the key mediators of hepatic carcinogenesis induced by CF and PBO, but PB appears to act via different mechanisms.
Topics: Animals; CD36 Antigens; Carcinogens; Clofibrate; Estrogen Receptor alpha; Female; Hepatomegaly; Leukemia Inhibitory Factor Receptor alpha Subunit; Liver; Male; Phenobarbital; Piperonyl Butoxide; RNA, Messenger; Rats; Rats, Inbred F344; Receptors, Androgen
PubMed: 22467018
DOI: 10.2131/jts.37.281