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Interventions for treating scabies.

BACKGROUND: Scabies is a common public health problem with an estimated prevalence of 300 million. Infestation can cause considerable discomfort and intense itching. Severe adverse effects have been reported for some drugs used to treat scabies. OBJECTIVES: The objective of this review is to assess the effects and toxicity of topical and systemic drug treatment for scabies. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, military records, traditional medicine databases. We also contacted international specialist centres and drug manufacturers. SELECTION CRITERIA: Randomised controlled trials of any drug treatment for scabies. Tolerability and toxicity were sought in any study of humans taking any drug treatments for scabies. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Eleven trials were included (7 compared drug treatments, 2 compared treatment regimes, 1 compared the drug vehicle and 1 was a community intervention). Compared with placebo in one small trial, ivermectin was associated with a significant higher clinical cure rate at seven days. Permethrin appeared to be more effective than crotamiton for clinical and parasitic cure rates. Permethrin appeared to be better than gamma benzene hexachloride for clinical cure rates in two small trials but had no advantage in the largest trial (test for heterogeneity p< 0.001). Permethrin also appeared more effective in reducing itch persistance than gamma benzene hexachloride. There appeared to be no difference in clinical cure rates between crotamiton and gamma benzene hexachloride. Single trials assessed: the effectiveness of oral versus topical treatment (ivermectin versus benzyl benzoate); treatment vehicle (pork fat versus cold cream); and mass community treatment (ivermectin) but were too small to demonstrate an effect. No randomised trials of malathion were identified. Serious adverse drug reactions (including death and convulsions) have been reported in other studies of scabies drugs, most notably gamma benzene hexachoride and ivermectin. REVIEWER'S CONCLUSIONS: The evidence that permethrin is more effective than gamma benzene hexachloride is inconsistent. Permethrin appears to have less potential serious drugs reactions than gamma benzene hexachloride although this is not derived from trial data. More research is needed of the safety and effectiveness of ivermectin and malathion compared to permethrin, on community management, and on different regimes and vehicles for topical treatment.

Hexachlorocyclohexane↗

Bioactive permethrin/beta-cyclodextrin inclusion complex.

Permethrin is popularly used in a variety of therapeutic areas. However, the poor water solubility of permethrin seriously limits its wider clinical applications. The present study demonstrates that solubility of permethrin in aqueous solution can considerably increase in the presence of beta-cyclodextrin (beta-CD). Extensive experimental data along with computational modeling reveal the formation of stable permethrin/beta-CD inclusion complexes, including permethrin(beta-CD) and permethrin(beta-CD)2, through hydrophobic binding. Both permethrin(beta-CD) and permethrin(beta-CD)2 complexes coexisted in aqueous solution, and the ratio of the concentration of permethrin(beta-CD) complex to that of permethrin(beta-CD)2 complex was dependent on the concentration of beta-CD. The complexation of permethrin with beta-CD significantly improved the bioavailability of permethrin and, therefore, increased the bioactivity. The significant increase of the bioactivity of permethrin in the presence of beta-CD provides an effective approach to improve the practical use of permethrin in public health and agriculture.

Calorimetry, Differential Scanning↗

Interventions for treating headlice.

BACKGROUND: Infection with head lice is a widespread condition in developed and developing countries. Infection occurs most commonly in children, but also affects adults. If left untreated the condition can become intensely irritating and skin infections may occur if the bites are scratched. OBJECTIVES: The aim of this review was to assess the effects of interventions for head lice. SEARCH STRATEGY: Trials register of The Cochrane Infectious Diseases Group; Medline; Embase; Science Citation Index; Biosis and Toxline; reference lists of relevant articles; pharmaceutical companies producing pediculicides (published and unpublished trials); UK and US Regulatory Authorities. SELECTION CRITERIA: Randomised trials (published and unpublished) or trials using alternate allocation were sought which compared pediculicides with the same and different formulations of other pediculicides, and pediculicides with physical methods. DATA COLLECTION AND ANALYSIS: Of the 70 identified studies, only three met the inclusion criteria and one is awaiting assessment. Two reviewers independently assessed trial quality. One reviewer extracted the data. MAIN RESULTS: We found no evidence that any one pediculicide has greater effect than another. The two studies comparing malathion and permethrin with their respective vehicles showed a higher cure rate for the active ingredient than the vehicle. The third study comparing synergised pyrethrins with permethrin showed their effects to be equivalent. Adverse effects were reported in a number of trials and were all minor, although reporting quality varied between trials. REVIEWER'S CONCLUSIONS: Permethrin, synergised pyrethrin and malathion were effective in the treatment of head lice. However, the emergence of drug resistance since these trials were conducted means there is no direct contemporary evidence of the comparative effectiveness of these products. The 'best' choice will now depend on local resistance patterns. There is currently no evidence from trials to indicate the effectiveness of physical methods, such as combing/'BugBusting' or other chemical control methods such as the use of herbal treatments, when used in the curative treatment of head lice. Future trials should take into account the methodological recommendations that arise from this review.

Adult↗

Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures.

Numerous xenobiotics are capable of inducing their own metabolism and by enzyme induction can also lead to enhanced biotransformation of other xenobiotics. In this project, we examined the influence of pyrethroids (permethrin, cypermethrin, and fenvalerate) on the expression and activity of the phenobarbital (PB)-inducible cytochrome P450 2B1 isoform (CYP2B1) in primary rat hepatocyte cultures. Incubation of hepatocyte cultures with pyrethroids resulted in a marked CYP2B1 induction. Among the tested pyrethroids, permethrin elicited the most pronounced induction of CYP2B1 mRNA, which exceeded maximal induction achieved by PB at concentrations approximately 10-fold higher. Furthermore, permethrin induced CYP3A1 mRNA expression, while the expression of the CYP1A1 isoform, which in vivo is not responsive to PB treatment, was not significantly affected by pyrethroids. Permethrin-dependent enhancement of CYP2B1 and CYP3A1 mRNA expression was repressed by the hepatotrophic cytokine epidermal growth factor, which is known to also inhibit PB-dependent induction of CYP2B1. Several metabolites of permethrin formed by hepatocytes (3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid) were ineffective in inducing CYP2B1 mRNA. Furthermore, permethrin stimulated the expression of the luciferase reporter gene under control of the CYP2B1 promoter (comprising the PB-responsive enhancer module) in transiently transfected primary hepatocyte cultures. Thus, permethrin-stimulated gene expression occurred on the transcriptional level. Taken together, these results indicate that the pyrethroid permethrin is a PB-like inducer. Due to its superior potency in induction, permethrin appears as a useful substance for mechanistic studies to elucidate the mechanism of enzyme induction by phenobarbital.

Animals↗

Repression of activity-dependent c-fos and brain-derived neurotrophic factor mRNA expression by pyrethroid insecticides accompanying a decrease in Ca(2+) influx into neurons.

Permethrin, a type I pyrethroid insecticide, is known to affect sodium channels of neurons and prolong sodium currents. On the other hand, the expression of brain-derived neurotrophic factor (BDNF) and c-fos genes is activated through Ca(2+) influx into neurons, in an activity-dependent manner. In this study, therefore, we investigated whether permethrin influenced the Ca(2+) signal-induced expression of these genes. In primary culture of mouse cerebellar granule cells (CGCs), stimulation with veratridine, a potent agonist for sodium channels, which causes membrane depolarization in neurons, induced c-fos and BDNF mRNA expression accompanying the Ca(2+) influx into neurons. Pretreatment with permethrin at doses nontoxic to CGCs repressed the induction of these genes dose dependently, with trans-permethrin more potent than cis-permethrin. Consistent with this, the increase in Ca(2+) influx caused by veratridine was repressed by permethrin. The membrane depolarization induced by elevating the potassium (K(+)) concentration in medium (high K(+)) caused the activation of c-fos and BDNF genes, which was also repressed by permethrin. Immunoblotting analysis of c-Fos and a gel-mobility assay of AP-1 DNA-binding activity supported the decrease in c-Fos synthesis in permethrin-treated CGCs. The type II pyrethroid cypermethrin also affected the expression of these genes but less effectively than permethrin. Thus, pyrethroids inhibit the activity-dependent gene expression in neurons.

Animals↗

Biochemical detection of pyrethroid resistance mechanism in Aedes aegypti in Ratchaburi province, Thailand.

The emergence of insecticide resistance in mosquito vectors was an important issue to be considered as one of factors influencing the success of vector control. The early detection of resistance could help the health personnel to plan and select appropriate alternative control measures or insecticide for effective control. Therefore biochemical assay of enzymes in mosquito was conducted to detect the emergence of insecticide resistance and to define the machanisms involved in pyrethroid resistance. Adults of Aedes aegypti from two localtities in Ratchaburi province were subjected to permethrin and deltamethrin selection in laboratory. After three generations of selection, permethrin-selected and deltamethrin-selected strains were established. Their LT 50 increased to 7.46 and 1.18 folds in the F3 strains that were selected with permethrin and deltamethrin respectively. The enzymes of these mosquitoes were assayed biochemically to study the mechanisms of resistance. The results revealed significant increase of esterase activity and monooxygenase levels in both strains when compared with labolatory susceptible strain. Glutathione-S-transferase activity was found to increase in permethrin-selected strain but not in deltamethrin-selected strain. This suggested that not only esterase and monooxygenase but also glutathione-S-transferase were associated with permethrin resistance in Ae. aegypti. The exposing of permethrin-selected and deltamethrin-selected mosquitoes to diagnostic concentration of permethrin (0.75%) and deltamethrin (0.05%) indicated no cross resistance for permethrin to deltamethrin while slight cross resistance from deltamethrin to permethrin was evident. It seemed that glutathione S-tranferase was not associated with cross resistance since its activity in deltamethrin-selected strain remained unchanged as compared with that of laboratory susceptible strain.

Journal Article↗

Resistance in the mosquito, Culex quinquefasciatus, and possible mechanisms for resistance.

Two mosquito strains of Culex quinquefasciatus (Say), MAmCq(G0) and HAmCq(G0), were collected from Mobile and Huntsville, Alabama, respectively. MAmCq(G0) and HAmCq(G0) were further selected in the laboratory with permethrin for one and three generations, respectively. The levels of resistance to permethrin in MAmCq(G1) (after one-generation selection) and HAmCq(G3) (after three-generation selection) increased rapidly. Resistance to permethrin in MAmCq(G1) and HAmCq(G3) was partially suppressed by piperonyl butoxide (PBO), S,S,S-tributylphosphorotrithioate (DEF) and diethyl maleate (DEM), inhibitors of cytochrome P450 monooxygenases, hydrolases and glutathione S-transferases (GST), respectively, suggesting these three enzyme families are important in conferring permethrin resistance in both strains. A substitution of leucine to phenylalanine (L to F) resulting from a single nucleotide polymorphism (SNP), termed the kdr mutation, in the para-homologous sodium channel gene has been reported as a very common mutation associated with pyrethroid resistance of insects. A 341-bp sodium channel gene fragment, where the kdr mutation resides, was generated by PCR from genomic DNAs of Cx. quinquefasciatus strains. We found that the kdr mutation was present in both permethrin-selected and unselected HAmCq and MAmCq mosquito populations, suggesting that the kdr mutation plays the role in permethrin resistance. There was no significant change in the frequency and heterozygosity of the A to T SNP for the kdr allele between permethrin-selected and unselected MAmCq and HAmCq mosquitoes, indicating that other mechanisms are involved in the evolution of resistance in mosquitoes selected by permethrin in the laboratory.

Animals↗

Indoor pyrethroid exposure in homes with woollen textile floor coverings.

In order to investigate human's exposure to permethrin from treated woollen textile floor coverings and possible adverse health effects, a study was carried out in 80 private homes in Hannover (Germany) equipped with woollen textile floor coverings (wool wall-to-wall carpets or woven or knotted rugs). For indoor monitoring, permethrin was determined both in house dust and on suspended particles. While permethrin concentrations in house dust (< 2 mm) were high (arithmetic mean: 53.7 mg/kg, 90th percentile 129.1 mg/kg), the permethrin concentrations in the air (suspended particles) were very low (arithmetic mean 2.8 ng/m3, 90th percentile 5.8 ng/m3, first sampling). Additional experiments demonstrate that permethrin on suspended particles result from carpet fiber abrasion (and not from an evaporation/re-condensation process). The internal exposure of the 145 inhabitants participating in the study was determined by biological monitoring (permethrin metabolites in urine). In a first sampling period almost 14% of the samples showed concentrations of the metabolite DCCA and almost 23% of the metabolite 3-PBA above the limit of detection (0.2 microgram/l). A model was developed which allows the calculation of the metabolite concentration in urine due to inhalative uptake of permethrin. Even for the worst case situation the calculated metabolite concentrations were ca. 30 times lower than the experimental results. The observed concentrations of metabolites are comparable to those of the background concentrations of the general population in Germany, suggesting that they must origin from other sources than woollen textile floor coverings. The indoor and biological monitoring data as well as the evaluation of the reported symptoms give no indication of an adverse health effect due to carpet treatment by permethrin.

Adult↗

Behavioral response of host-seeking mosquitoes (Diptera: Culicidae) to insecticide-impregnated bed netting: a new approach to insecticide bioassays.

The response of Anopheles gambiae Giles s.s and Culex quinquefasciatus Say to insecticide-treated netting in a wind tunnel permeated with guinea pig odors was recorded on videotape. With no insecticide present, mosquitoes spent 99% of the time on the netting, either at rest or occasionally walking across it. On nylon netting, permethrin at 50, 400, and 1,000 mg m-2 irritated the mosquitoes, causing them to spend significantly more time away from the netting and relatively more time walking than at rest when they were on the netting. These effects increased with dose, but the total contact time was always enough to cause 100% mortality. At the two highest doses, knockdown occurred before the end of the 10-min observation period. A wash-resistant formulation of permethrin (ICI patent) reduced irritancy without affecting mortality or knockdown. A mixture of pirimiphos-methyl and permethrin also was less irritating than permethrin alone. Pirimiphos-methyl at 400 mg m-2 was the least irritating of all treatments tested. Lambda-cyhalothrin at 2.5, 6, and 25 mg m-2 was less irritating than permethrin, even though the doses of lambda-cyhalothrin used were far more toxic than the permethrin doses as measured by LT50. Cotton netting significantly reduced the toxicity and irritancy of the permethrin treatments. Cx. quinquefasciatus was less irritated by permethrin but more irritated by lambda-cyhalothrin, than was An. gambiae. Our study indicated that mosquitoes are so strongly attracted to a host protected by netting, they will tolerate relatively high doses of irritating insecticides long enough to pick up lethal doses.

Animals↗

Modifications of pyrethroid effects associated with kdr mutation in Anopheles gambiae.

Effects of knockdown resistance (kdr) were investigated in three pyrethroid-resistant (RR) strains of the Afrotropical mosquito Anopheles gambiae Giles (Diptera: Culicidae): Kou from Burkina Faso, Tola and Yao from Côte d'Ivoire; compared with a standard susceptible (SS) strain from Kisumu, Kenya. The kdr factor was incompletely recessive, conferring 43-fold resistance ratio at LD50 level and 29-fold at LD95 level, as determined by topical application tests with Kou strain. When adult mosquitoes were exposed to 0.25% permethrin-impregnated papers, the 50% and 95% knockdown times (KdT) were 23 and 42 min for SS females, compared with 40 and 62 min for RS (F1 Kou x Kisumu) females. On 1% permethrin the KdT50 and KdT95 were 11 and 21 min for SS compared with 18 and 33 min for RS females. Following 1 h exposure to permethrin (0.25% or 1%), no significant knockdown of Kou RR females occurred within 24 h. Permethrin irritancy to An. gambiae was assessed by comparing 'time to first take-off' (TO) for females. The standard TO50 and TO95 values for Kisumu SS on untreated paper were 58 and 1044 s, respectively, vs. 3.7 and 16.5 s on 1% permethrin. For Kou RR females the comparable values were 27.3 s for TO50 and 294 s for TO95, with intermediate RS values of 10.1 s for TO50 and 71.9 s for TO95. Thus, TO values for RS were 2.7-4.4 times more than for SS, and those for RR were 7-18 times longer than for SS. Experiments with pyrethroid-impregnated nets were designed to induce hungry female mosquitoes to pass through holes cut in the netting. Laboratory 'tunnel tests' used a bait guinea-pig to attract mosquitoes through circular holes (5 x 1 cm) in a net screen. With untreated netting, 75-83% of laboratory-reared females passed through the holes overnight, 63-69% blood-fed successfully and 9-17% died, with no significant differences between SS and RR genotypes. When the netting was treated with permethrin 250mg ai/m2 the proportions that passed through the holes overnight were only 10% of SS vs. 40-46% of RR (Tola & Kou); mortality rates were 100% of SS compared with 59-82% of RR; bloodmeals were obtained by 9% of Kou RR and 17% of Tola RR, but none of the Kisumu SS females. When the net was treated with deltamethrin 25 mg ai/m2 the proportions of An. gambiae that went through the holes and blood-fed successfully were 3.9% of Kisumu SS and 3.5% of Yaokoffikro field population (94% R). Mortality rates were 97% of Kisumu SS vs. 47% of Yaokoffikro R. Evidently this deltamethrin treatment was sufficient to kill nearly all SS and half of the Yaokoffikro R An. gambiae population despite its high kdr frequency. Experimental huts at Yaokoffikro were used for overnight evaluation of bednets against An. gambiae females. The huts were sealed to prevent egress of mosquitoes released at 20.00 hours and collected at 05.00 hours. Each net was perforated with 225 square holes (2 x 2 cm). A man slept under the net as bait. With untreated nets, only 4-6% of mosquitoes died overnight and bloodmeals were taken by 17% of SS vs. 29% of Yaokoffikro R (P<0.05). Nets treated with permethrin 500 mg/m2 caused mortality rates of 95% Kisumu SS and 45% Yao R (P<0.001) and blood-feeding rates were reduced to 1.3% of SS vs. 8.1% of Yao R (P<0.05). Nets treated with deltamethrin 25 mg/m2 caused mortality rates of 91% Kisumu SS and 54% Yao R (P<0.001) and reduced blood-feeding rates to zero for SS vs. 2.5% for Yao R (P>0.05). (ABSTRACT TRUNCATED)

Animals↗

Pyrethroid-treated bednet effects on mosquitoes of the Anopheles gambiae complex in The Gambia.

The response of Anopheles gambiae complex mosquitoes to men sleeping under insecticide-impregnated or untreated bednets in six verandah trap huts was studied during the dry season in The Gambia. With this type of hut it was possible to collect live and dead indoor-resting mosquitoes and estimate the number of wild mosquitoes which entered, bloodfed on man, and exited each night. Bednets were treated with emulsions targetted to leave deposits of 25 mg/m2 lambda-cyhalothrin, or 5, 50 or 500 mg/m2 permethrin, diluted from emulsifiable concentrates (EC), or a blank formulation similar to the EC except that the permethrin was omitted; the sixth net was left untreated. Nets and sleepers were rotated between huts on different nights, the design being based on a series of Latin squares and conducted double-blind. Permethrin-impregnated bednets deterred mosquitoes from entering the huts. The degree of deterrency was proportional to the dosage of permethrin. This effect was also caused by the blank formulation and therefore attributed to other components of the formulation, rather than to the permethrin itself. The net impregnated with 500 mg permethrin per square metre gave the best individual protection, reducing mosquito bloodfeeding by 91% compared with untreated nets. However, lambda-cyhalothrin was proportionately more insecticidal than permethrin at doses of equivalent deterrency. At this stage of research, it remains conjectural whether chemical deterrency or killing of malaria vectors is better for community protection.

Animals↗

Isolation and identification of an esterase from a Mexican strain of Boophilus microplus (Acari: Ixodidae).

A strain of Mexican Boophilus microplus (Cz) collected near Coatzacoalcos, Veracruz, Mexico, exhibits a moderate, but significant, level of permethrin resistance. Unlike other highly permethrin resistant strains, the Cz strain does not have a mutation within the sodium channel gene that results in target-site insensitivity. However, the Cz strain possesses a substantial increase in general and permethrin esterase activity relative to highly permethrin resistant and control strains suggesting the involvement of a metabolic esterase(s) in the expression of permethrin resistance. We report the isolation of a 62.8 kDa protein from Cz strain larvae that we think is the esterase previously reported as Cz EST9. In addition, internal amino acid sequence data obtained from the 62.8 kDa protein suggest that it is the gene product of a previously reported B. microplus carboxylesterase cDNA. We propose that the 62.8 kDa protein (Cz EST9) has permethrin hydrolytic activity and as a result plays an important role in Cz strain resistance to permethrin.

Amino Acid Sequence↗

Development of Wuchereria bancrofti in Culex pipiens L. (Diptera: Culicidae) exposed in the larval instar to sublethal dosages of insecticides and one insect growth regulator and their influence on reproduction of filaria-infected mosquitoes.

The effects of exposure of Culex pipiens larvae to sublethel concentrations of larvicides on uptake, development of Wuchereria bancrofti, survival rate and reproduction of filaria-infected mosquitoes were investigated. Fourth instar larvae of Cx. pipiens were exposed to LC40 of the surfactant Triton X-100, the insect growth regulator DPX alone or combined with LC10 of the surfactant and permethrin alone or combined with LC10 of the surfactant. Adults that survived insecticide treatments and controls were infected by allowing them to feed on microfilaremic volunteers. Significant reduction in the uptake of microfilaria was observed in groups treated with Triton X-100 alone or combined either with permethrin or DPX when compared to control. The overall infection and infective rates were significantly reduced in mosquitoes treated with Triton X-100 either alone or combined with permethrin. Treatment with Triton X-100 and DPX prolonged the extrinsic incubation period (EIP) and retarded the development of filarial larvae, while permethrin either alone or combined with Triton X-100 and DPX combined with Triton X-100 shortened the EIP. All larvicides reduced the number of infective larvae (L3)/mosquito and induced deformities among he different parasite stages, especially in mosquitoes treated with combination of permethrin and Triton X-100 or mixture of DPX and Triton X-100 where 36% and 54.9% respectively of L3S were deformed. In treated mosquitoes, a low percentage of L3S was detected in the head and proboscis region while the majority was trapped in the thoracic region. The survival rates of mosquitoes were reduced in cases treated with permethrin, DPX and Triton X-100 while treatment with mixture of DPX and Triton X-100 induced higher rate of mortalities when compared to control. Egg production of filaria- infected Cx. pipiens was significantly reduced in mosquitoes treated with DPX and Triton X-100. It was observed that the addition of Triton X-100 to DPX or to permethrin significantly reduced egg production. The results suggest that sublethal concentrations of larvicides especially Triton X-100 applied to 4th instar larvae of Cx. pipiens could effectively interfere with the development of W. bancrofti in Cx. pipiens and reduced the survival rate and fecundity of the vector.

Animals↗

[Pyrethroids in house dust of the German housing population--results of 2 nationwide cross-sectional studies].

As a part of the German Environmental Surveys performed in 1985/86 (West Germany), 1990/91 (West Germany) and 1991/92 (East Germany), dust samples were collected in the households of about 1600 randomly selected adults (25 to 69 years) and an analysis of these samples was performed in respect of their content of 8 different pyrethroids and of the synergist piperonyl butoxide (PBO). In the 1990-92 survey about 90% of the samples contained permethrin in concentrations above the limit of quantification. This showed permethrin to be the most widespread of the 8 compounds investigated. The geometric mean of the permethrin content in domestic dust was 0.22 mg/kg. Only about 8% of the samples contained one or more of the other investigated substances (cyfluthrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, deltamethrin, empenthrin, d-phenothrin) in quantifiable amounts. About 76% of the samples contained quantifiable amounts of PBO. In East Germany the geometric mean of the PBO content (0.21 mg/kg) was significantly higher than in West Germany (0.07 mg/kg), but no difference for permethrin was found. Significant associations could be shown for the permethrin content and the application of biocides as well as for the PBO content and regional factors (size of community, type of dwelling area). Samples collected in 1985/86 (West Germany) showed a geometric mean for permethrin of 0.06 mg/kg and for PBO of 0.07 mg/kg. Comparing the values of 1985/86 and 1990/91, a significant increase can be observed for permethrin, whereas the PBO concentration remained constant.

Adult↗

Identification of a point mutation in the voltage-gated sodium channel gene of Kenyan Anopheles gambiae associated with resistance to DDT and pyrethroids.

A field trial of permethrin-impregnated bednets and curtains was initiated in Western Kenya in 1990, and a strain of Anopheles gambiae showing reduced susceptibility to permethrin was colonized from this site in 1992. A leucine-phenylalanine substitution at position 1014 of the voltage-gated sodium channel is associated with resistance to permethrin and DDT in many insect species, including Anopheles gambiae from West Africa. We cloned and sequenced a partial sodium channel cDNA from the Kenyan permethrin-resistant strain and we identified an alternative substitution (leucine to serine) at the same position, which is linked to the inheritance of permethrin resistance in the F(2) progeny of genetic crosses between susceptible and resistant individuals. The diagnostic polymerase chain reaction (PCR) developed by Martinez-Torres et al. [(1998) Insect Mol Biol 7: 179-184] to detect kdr alleles in field populations of An. gambiae will not detect the Kenyan allele and hence reliance on this assay may lead to an underestimate of the prevalence of pyrethroid resistance in this species. We adapted the diagnostic PCR to detect the leucine-serine mutation and with this diagnostic we were able to demonstrate that this kdr allele was present in individuals collected from the Kenyan trial site in 1986, prior to the introduction of pyrethroid-impregnated bednets. The An. gambiae sodium channel was physically mapped to chromosome 2L, division 20C. This position corresponds to the location of a major quantitative trait locus determining resistance to permethrin in the Kenyan strain of An. gambiae.

Amino Acid Substitution↗

Effects of daily dermal application of DEET and epermethrin, alone and in combination, on sensorimotor performance, blood-brain barrier, and blood-testis barrier in rats.

DEET and permethrin were implicated in the development of illnesses in some veterans of the Persian Gulf War. This study was designed to investigate the effects of daily dermal application of these chemicals, alone or in combination, on the permeability of the blood-brain barrier (BBB) and blood-testes barrier (BTB) and on sensorimotor performance in male Sprague-Dawley rats. Groups of five rats were treated with a dermal daily dose of 4, 40, or 400 mg/kg DEET in ethanol or 0.013, 0.13, or 1.3 mg/kg permethrin in ethanol for 60 d. A group of 10 rats received a daily dermal dose of ethanol and served as controls. BBB permeability was assessed by injection of an iv dose of the quaternary ammonium compound [3H]hexamethonium iodide. While permethrin produced no effect on BBB permeability, DEET alone caused a decrease in BBB permeability in brainstem. A combination of DEET and permethrin significantly decreased the BBB permeability in the cortex. BTB permeability was decreased by treatment with DEET alone and in combination with permethrin. The same animals underwent a battery of functional behavior tests 30, 45, and 60 d after exposure to evaluate their sensorimotor abilities. All treatments caused a significant decline in sensorimotor performance in a dose- and time-dependent manner. These results show that daily dermal exposure to DEET, alone or in combination with permethrin, decreased BBB permeability in certain brain regions, and impaired sensorimotor performance.

Administration, Topical↗