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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 -
Veterinary Parasitology May 2023Control of flystrike on sheep relies on the use of insecticides. The present study used in vitro assays to examine the potential for increasing the efficacy of synthetic...
Reduced synergistic efficacy of piperonyl butoxide in combination with alpha-cypermethrin in vitro in an insecticide-resistant strain of the sheep blowfly, Lucilia cuprina.
Control of flystrike on sheep relies on the use of insecticides. The present study used in vitro assays to examine the potential for increasing the efficacy of synthetic pyrethroids against sheep blowfly larvae using the synergist piperonyl butoxide (PBO). We examined the potency of alpha-cypermethrin (ACP) / PBO combinations against a reference insecticide-susceptible strain (LS) and a field-derived strain showing resistance to dicyclanil and imidacloprid. Co-treatment of the insecticide-susceptible strain with ACP/PBO resulted in increasing levels of synergism as the PBO concentration was increased, with synergism ratios (SRs) of up to 114-fold. Treatment with PBO/ACP combinations at ratios of 20:1 and 5:1 resulted in significant levels of synergism: SRs of 13.5- and 7.6-fold, respectively. However, the levels of synergism were significantly less for the insecticide-resistant strain: SRs of 4.6- and 2.6-fold for the 20:1 and 5:1 ratios, respectively. The resistant strain showed no resistance to ACP when administered alone, however, was 2-fold less sensitive than the LS strain to the toxic effects of PBO alone. This insensitivity to PBO was removed by co-treatment with the P450 inhibitor aminobenzotriazole, suggesting an increased level of P450-mediated metabolism of the PBO in this strain compared to the LS strain, and hence providing a likely explanation for the reduced synergistic efficacy of PBO on ACP toxicity in the resistant strain. While PBO was able to synergise ACP with both of the blowfly strains examined here, the reduced synergistic efficacy observed with the field-derived insecticide-resistant strain lessens the potential usefulness of such a combination for blowfly control in the field.
Topics: Animals; Insecticides; Piperonyl Butoxide; Insecticide Resistance; Calliphoridae; Pesticide Synergists; Pyrethrins; Diptera
PubMed: 37001325
DOI: 10.1016/j.vetpar.2023.109917 -
The American Journal of Tropical... Oct 2022The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM) has been conducting malaria research in Uganda since 2010 to improve the...
The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM) has been conducting malaria research in Uganda since 2010 to improve the understanding of the disease and measure the impact of population-level control interventions in the country. Here, we will summarize key research findings from a series of studies addressing routine health facility-based surveillance, comprehensive cohort studies, studies of the molecular epidemiology, and transmission of malaria, evaluation of antimalarial drug efficacy, and resistance across the country, and assessments of insecticide resistance. Among our key findings are the following. First, we found that in historically high transmission areas of Uganda, a combination of universal distribution of long-lasting insecticidal-treated nets (LLINs) and sustained indoor residual spraying (IRS) of insecticides lowered the malaria burden greatly, but marked resurgences occurred if IRS was discontinued. Second, submicroscopic infections are common and key drivers of malaria transmission, especially in school-age children (5-15 years). Third, markers of drug resistance have changed over time, with new concerning emergence of markers predicting resistance to artemisinin antimalarials. Fourth, insecticide resistance monitoring has demonstrated high levels of resistance to pyrethroids, appreciable impact of the synergist piperonyl butoxide to pyrethroid susceptibility, emerging resistance to carbamates, and complete susceptibility of malaria vectors to organophosphates, which could have important implications for vector control interventions. Overall, PRISM has yielded a wealth of information informing researchers and policy-makers on the malaria burden and opportunities for improved malaria control and eventual elimination in Uganda. Continued studies concerning all the types of surveillance discussed above are ongoing.
Topics: Adolescent; Animals; Antimalarials; Artemisinins; Carbamates; Child; Child, Preschool; Humans; Insecticide Resistance; Insecticide-Treated Bednets; Insecticides; Malaria; Mosquito Control; Mosquito Vectors; Organophosphates; Piperonyl Butoxide; Pyrethrins; Uganda
PubMed: 36228916
DOI: 10.4269/ajtmh.21-1285 -
Journal of Pesticide Science Nov 2023Four nitromethylene analogues of imidacloprid (CH-IMIs) having a 4,5-dimethylated (diMe) imidazolidine ring were stereospecifically synthesized to evaluate their...
Four nitromethylene analogues of imidacloprid (CH-IMIs) having a 4,5-dimethylated (diMe) imidazolidine ring were stereospecifically synthesized to evaluate their affinity for the nicotinic acetylcholine receptors of the housefly . Among the analogues, the 4,5-diMe analogue showed the highest receptor affinity (=0.39 nM). The insecticidal activity against of the synthesized compounds was also measured under synergistic and nonsynergistic conditions. Under nonsynergistic conditions, the insecticidal activity of the 4,5-diMe analogue was the highest. The order of the insecticidal potency of the four diMe-CH-IMIs (4,5->4,5-=4,5->4,5-diMe analogues) was the same as that of the receptor affinity. Piperonyl butoxide (PBO) did not synergize with the test compounds, but both PBO and NIA16388 applications strengthened the activity of analogues other than the 4,5-diMe analogue. This suggests that the configuration of the substituents on the imidazolidine ring should influence the metabolism process of CH-IMI in houseflies.
PubMed: 38090215
DOI: 10.1584/jpestics.D23-024 -
PloS One 2017Isoxadifen-ethyl can effectively alleviate nicosulfuron injury in the maize. However, the effects of safener isoxadifen-ethyl on detoxifying enzymes in maize is unknown....
Isoxadifen-ethyl can effectively alleviate nicosulfuron injury in the maize. However, the effects of safener isoxadifen-ethyl on detoxifying enzymes in maize is unknown. The individual and combined effects of the sulfonylurea herbicide nicosulfuron and the safener isoxadifen-ethyl on the growth and selected physiological processes of maize were evaluated. Bioassays showed that the EC50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for maize cultivar Zhengdan958 were 18.87 and 249.28 mg kg-1, respectively, and were 24.8 and 275.51 mg kg-1, respectively, for Zhenghuangnuo No. 2 cultivar. Evaluations of the target enzyme of acetolactate synthase showed that the I50 values of nicosulfuron and nicosulfuron plus isoxadifen-ethyl for the ALS of Zhengdan958 were 15.46 and 28.56 μmol L-1, respectively, and were 0.57 and 2.17 μmol L-1, respectively, for the acetolactate synthase of Zhenghuangnuo No. 2. The safener isoxadifen-ethyl significantly enhanced tolerance of maize to nicosulfuron. The enhanced tolerance of maize to nicosulfuron in the presence of the safener, coupled with the enhanced injury observed in the presence of piperonyl butoxide, 1-aminobenzotriazole, and malathion, suggested cytochrome P450 monooxygenases may be involved in metabolism of nicosulfuron. We proposed that isoxadifen-ethyl increases plant metabolism of nicosulfuron through non-P450-catalyzed routes or through P450 monooxygenases not inhibited by piperonyl butoxide, 1-aminobenzotriazole, and malathion. Isoxadifen-ethyl, at a rate of 33 mg kg-1, completely reversed the effects of all doses (37.5-300 mg kg-1) of nicosulfuron on both of the maize cultivars. When the two compounds were given simultaneously, isoxadifen-ethyl enhanced activity of glutathione S-transferases (GSTs) and acetolactate synthase activity in maize. The free acid 4,5-dihydro-5,5-diphenyl-1,2-oxazole-3-carboxylic was equally effective at inducing GSTs as the parent ester and appeared to be the active safener. GST induction in the maize Zhenghuangnuo No. 2 was faster than in Zhengdan 958.
Topics: Acetolactate Synthase; Cytochrome P-450 Enzyme System; Enzyme Activation; Glutathione; Glutathione Transferase; Inactivation, Metabolic; Oxazoles; Plant Shoots; Pyridines; Seedlings; Sulfonylurea Compounds; Zea mays
PubMed: 28267798
DOI: 10.1371/journal.pone.0173502 -
Malaria Journal Dec 2022Mass distribution of insecticide-treated nets (ITNs) is the principal malaria vector control strategy adopted by Niger. To better inform on the most appropriate ITN to...
BACKGROUND
Mass distribution of insecticide-treated nets (ITNs) is the principal malaria vector control strategy adopted by Niger. To better inform on the most appropriate ITN to distribute, the National Malaria Control Programme (NMCP) of Niger and its partners, conducted insecticide resistance monitoring in selected sites across the country.
METHODS
The susceptibility of Anopheles gambiae sensu lato (s.l.) to chlorfenapyr and pyrethroid insecticides was investigated in a total of sixteen sites in 2019 and 2020, using 2-5-day-old adults reared from wild collected larvae per site. The susceptibility status, pyrethroid resistance intensity at 5 and 10 times the diagnostic concentrations, and piperonyl butoxide (PBO) synergism with diagnostic concentrations of deltamethrin, permethrin and alpha-cypermethrin were assessed using WHO bioassays. Two doses (100 and 200 µg/bottle) of chlorfenapyr were tested using the CDC bottle assay method. Species composition and allele frequencies for knock-down resistance (kdr-L1014F and L1014S) and acetylcholinesterase (ace-1 G119S) mutations were further characterized using polymerase chain reaction (PCR).
RESULTS
High resistance intensity to all pyrethroids tested was observed in all sites except for alpha-cypermethrin in Gaya and Tessaoua and permethrin in Gaya in 2019 recording moderate resistance intensity. Similarly, Balleyara, Keita and Tillabery yielded moderate resistance intensity for alpha-cypermethrin and deltamethrin, and Niamey V low resistance intensity against deltamethrin and permethrin in 2020. Pre-exposure to PBO substantially increased susceptibility with average increases in mortality between 0 and 70% for tested pyrethroids. Susceptibility to chlorfenapyr (100 µg/bottle) was recorded in all sites except in Tessaoua and Magaria where susceptibility was recorded at the dose of 200 µg/bottle. Anopheles coluzzii was the predominant malaria vector species in most of the sites followed by An. gambiae sensu stricto (s.s.) and Anopheles arabiensis. The kdr-L1014S allele, investigated for the first time, was detected in the country. Both kdr-L1014F (frequencies [0.46-0.81]) and L1014S (frequencies [0.41-0.87]) were present in all sites while the ace-1 G119S was between 0.08 and 0.20.
CONCLUSION
The data collected will guide the NMCP in making evidence-based decisions to better adapt vector control strategies and insecticide resistance management in Niger, starting with mass distribution of new generation ITNs such as interceptor G2 and PBO ITNs.
Topics: Animals; Insecticide Resistance; Anopheles; Permethrin; Acetylcholinesterase; Niger; Mosquito Vectors; Malaria; Pyrethrins; Insecticides; Africa, Western
PubMed: 36522727
DOI: 10.1186/s12936-022-04410-4 -
BioRxiv : the Preprint Server For... Apr 2023Neonicotinoids are potential alternatives for targeting pyrethroid-resistant mosquitoes, but their efficacy against malaria vector populations of Sub-Saharan Africa has...
BACKGROUND
Neonicotinoids are potential alternatives for targeting pyrethroid-resistant mosquitoes, but their efficacy against malaria vector populations of Sub-Saharan Africa has yet to be investigated. Here we tested and compared the efficacy of four neonicotinoids alone or in combination with a synergist against two major vectors of .
RESULTS
Using standard bioassays, we first assessed the lethal toxicity of three active ingredients against adults of two susceptible strains and we determined discriminating doses for monitoring susceptibility in wild populations. We then tested the susceptibility of 5532 mosquitoes collected from urban and rural areas of Yaoundé, Cameroon, to discriminating doses of acetamiprid, imidacloprid, clothianidin and thiamethoxam. We found that in comparison with some public health insecticides, neonicotinoids have high lethal concentration, LC , reflecting their low toxicity to mosquitoes. In addition to this reduced toxicity, resistance to the four neonicotinoids tested was detected in populations collected from agricultural areas where larvae are intensively exposed to crop-protection neonicotinoids. However, adults of another major vector that occurred in urbanized settings, , were fully susceptible to neonicotinoids except acetamiprid for which 80% mortality was obtained within 72 h of insecticide exposure. Importantly, the cytochrome inhibitor, piperonyl butoxide (PBO), was very effective in enhancing the activity of clothianidin and acetamiprid providing opportunities to create potent neonicotinoid formulations against .
CONCLUSION
These findings suggest that to successfully repurpose agricultural neonicotinoids for malaria vector control, it is essential to use formulations containing synergists such as PBO or surfactants to ensure optimal efficacy.
PubMed: 37131663
DOI: 10.1101/2023.04.18.537427 -
Journal of Bacteriology May 1971Staphylococcus aureus formed an electron transport system when exponentially growing cells were aerated. Formation of the electron transport system occurred...
Staphylococcus aureus formed an electron transport system when exponentially growing cells were aerated. Formation of the electron transport system occurred concomitantly with increases in the phospholipids and the carotenoids. The addition of piperonyl butoxide or benzo(a)pyrene at the onset of aeration (i) slowed the formation of the electron transport system, (ii) both inhibited cytochrome oxidase o synthesis and decreased its stability, (iii) simultaneously depressed the increase in total phospholipid (especially cardiolipin), and (iv) depressed the synthesis of the carotenoid rubixanthin. Benzo(a)pyrene was the more inhibitory of the two, both on the rate of synthesis of the electron transport system and on rubixanthin formation. Evidence obtained with the inhibitors suggested that inhibition of the lipid synthesis was related to the formation of the electron transport system.
Topics: Benzopyrenes; Carotenoids; Chromatography, Paper; Colorimetry; Culture Media; Cytochromes; Dioxoles; Electron Transport; Electron Transport Complex IV; Gels; Insecticides; Lipids; Oxygen; Phospholipids; Phosphorus Isotopes; Silicon Dioxide; Spectrophotometry; Staphylococcus
PubMed: 4324805
DOI: 10.1128/jb.106.2.403-411.1971 -
PloS One 2016Mosquito strains that exhibit increased tolerance to the chemical class of compounds with a sodium channel modulator mode of action (pyrethroids and pyrethrins) are...
BACKGROUND
Mosquito strains that exhibit increased tolerance to the chemical class of compounds with a sodium channel modulator mode of action (pyrethroids and pyrethrins) are typically described as "pyrethroid resistant". Resistance to pyrethroids is an increasingly important challenge in the control of mosquito-borne diseases, such as malaria or dengue, because one of the main interventions (the distribution of large numbers of long-lasting insecticide-treated bed nets) currently relies entirely on long-lasting pyrethroids. Increasing tolerance of target insects against this class of insecticides lowers their impact in vector control. The current study suggests that the level of metabolic resistance depends on the structure of the molecule and that structurally different compounds may still be effective because detoxifying enzymes are unable to bind to these uncommon structures.
METHODS
Treated surface contact bioassays were performed on susceptible Aedes aegypti, East African knockdown resistance (kdr) Anopheles gambiae (strain RSP-H) and metabolically resistant Anopheles funestus (strain FUMOZ-R) with different pyrethroids, such as cypermethrin, ß-cyfluthrin, deltamethrin, permethrin and transfluthrin (alone and in combination with the synergist piperonyl butoxide). The nonfluorinated form of transfluthrin was also assessed as a single agent and in combination with piperonyl butoxide.
RESULTS
Although the dosages for pyrethroids containing a phenoxybenzyl moiety have exhibited differences in terms of effectiveness among the three tested mosquito species, the structurally different transfluthrin with a polyfluorobenzyl moiety remained active in mosquitoes with upregulated P450 levels. In trials with transfluthrin mixed with piperonyl butoxide, the added synergist exhibited no efficacy-enhancing effect.
CONCLUSION
The results of this study suggest that transfluthrin has the potential to control P450-mediated metabolically resistant mosquitoes because the structural formula of transfluthrin differs from that of the tested pyrethroids, which are used in vector control. The P450-detoxifying enzymes of the Anopheles funestus FUMOZ-R mosquitoes seem to bind preferably at the phenoxybenzyl moiety and appear to be unable to degrade transfluthrin with its tetrafluorobenzyl moiety. Inhibition of the class of monooxygenases by piperonyl butoxide revealed no increase of efficacy of the pure transfluthrin compound, which also indicates that the P450 enzymes potentially do not impact the efficacy of transfluthrin.
Topics: Aedes; Animals; Anopheles; Binding Sites; Biological Assay; Cyclopropanes; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Fluorobenzenes; Insecticide Resistance; Insecticides; Molecular Structure; Mosquito Control; Nitriles; Permethrin; Pyrethrins; Reproducibility of Results
PubMed: 26930058
DOI: 10.1371/journal.pone.0149738