Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial.

BACKGROUND: Progress in malaria control is under threat by wide-scale insecticide resistance in malaria vectors. Two recent vector control products have been developed: a long-lasting insecticidal net that incorporates a synergist piperonyl butoxide (PBO) and a long-lasting indoor residual spraying formulation of the insecticide pirimiphos-methyl. We evaluated the effectiveness of PBO long-lasting insecticidal nets versus standard long-lasting insecticidal nets as single interventions and in combination with the indoor residual spraying of pirimiphos-methyl. METHODS: We did a four-group cluster randomised controlled trial using a two-by-two factorial design of 48 clusters derived from 40 villages in Muleba (Kagera, Tanzania). We randomly assigned these clusters using restricted randomisation to four groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, or PBO long-lasting insecticidal nets plus indoor residual spraying. Both standard and PBO nets were distributed in 2015. Indoor residual spraying was applied only once in 2015. We masked the inhabitants of each cluster to the type of nets received, as well as field staff who took blood samples. Neither the investigators nor the participants were masked to indoor residual spraying. The primary outcome was the prevalence of malaria infection in children aged 6 months to 14 years assessed by cross-sectional surveys at 4, 9, 16, and 21 months after intervention. The endpoint for assessment of indoor residual spraying was 9 months and PBO long-lasting insecticidal nets was 21 months. This trial is registered with ClinicalTrials.gov, number NCT02288637. FINDINGS: 7184 (68·0%) of 10 560 households were selected for post-intervention survey, and 15 469 (89·0%) of 17 377 eligible children from the four surveys were included in the intention-to-treat analysis. Of the 878 households visited in the two indoor residual spraying groups, 827 (94%) had been sprayed. Reported use of long-lasting insecticidal nets, across all groups, was 15 341 (77·3%) of 19 852 residents after 1 year, decreasing to 12 503 (59·2%) of 21 105 in the second year. Malaria infection prevalence after 9 months was lower in the two groups that received PBO long-lasting insecticidal nets than in the two groups that received standard long-lasting insecticidal nets (531 [29%] of 1852 children vs 767 [42%] of 1809; odds ratio [OR] 0·37, 95% CI 0·21-0·65; p=0·0011). At the same timepoint, malaria prevalence in the two groups that received indoor residual spraying was lower than in groups that did not receive indoor residual spraying (508 [28%] of 1846 children vs 790 [44%] of 1815; OR 0·33, 95% CI 0·19-0·55; p<0·0001) and there was evidence of an interaction between PBO long-lasting insecticidal nets and indoor residual spraying (OR 2·43, 95% CI 1·19-4·97; p=0·0158), indicating redundancy when combined. The PBO long-lasting insecticidal net effect was sustained after 21 months with a lower malaria prevalence than the standard long-lasting insecticidal net (865 [45%] of 1930 children vs 1255 [62%] of 2034; OR 0·40, 0·20-0·81; p=0·0122). INTERPRETATION: The PBO long-lasting insecticidal net and non-pyrethroid indoor residual spraying interventions showed improved control of malaria transmission compared with standard long-lasting insecticidal nets where pyrethroid resistance is prevalent and either intervention could be deployed to good effect. As a result, WHO has since recommended to increase coverage of PBO long-lasting insecticidal nets. Combining indoor residual spraying with pirimiphos-methyl and PBO long-lasting insecticidal nets provided no additional benefit compared with PBO long-lasting insecticidal nets alone or standard long-lasting insecticidal nets plus indoor residual spraying. FUNDING: UK Department for International Development, Medical Research Council, and Wellcome Trust.

The efficacy of Australian essential oils for the treatment of head lice infestation in children: A randomised controlled trial.

BACKGROUND: The increase in resistance of head lice to neurotoxic pediculicides and public concern over their safety has led to an increase in alternative treatments, many of which are poorly researched or even untested. METHODS: A multicentre, randomised, assessor-blind, parallel-group trial (Trial 1) was conducted to compare the safety and efficacy of a head lice treatment containing Australian eucalyptus oil and Leptospermum petersonii (EO/LP solution; applied thrice with 7-day intervals between applications) with a neurotoxic treatment containing pyrethrins and piperonyl butoxide (P/PB mousse; applied twice with a 7-day interval) in children. A single-blind, open trial (Trial 2) was conducted to assess the efficacy of EO/LP solution following a single application. In addition, skin irritancy and sensitisation tests using EO/LP solution were performed in adults and children. In vitro tests were performed to further assess the ovicidal and pediculicidal efficacy of EO/LP solution. RESULTS: EO/LP solution was found to be more than twice as effective in curing head lice infestation as P/PB mousse in per-protocol participants (Trial 1; 83% vs 36%, P < 0.0001), and was also found to be 100% pediculicidal following a single application (Trial 2). Adverse events were limited to transient itching, burning or stinging. Further skin testing with the EO/LP solution reported no irritation or sensitisation in adults, or irritation in children. In vitro exposure of lice and eggs to the EO/LP solution resulted in 100% mortality. CONCLUSION: The efficacy, safety and relative ease of use of the EO/LP solution make it a viable alternative in treating head lice.

Consequences of inhibition of bumetanide metabolism in rodents on brain penetration and effects of bumetanide in chronic models of epilepsy.

The diuretic bumetanide, which acts by blocking the Na-K-Cl cotransporter (NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N-butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (PBO) has previously been reported to increase the half-life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half-life 47 min vs. 13 min). Pretreatment with PBO increased the half-life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose-dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.

North American efficacy and safety of a novel pediculicide rinse, isopropyl myristate 50% (Resultz).

BACKGROUND: Head lice infestations are a major nuisance in school-aged children and are a worldwide public health problem. There are growing concerns about the effectiveness of current treatments owing to increasing resistance, safety, and patient noncompliance. A safe, easy to use, effective alternative is needed. OBJECTIVE: A pediculicide rinse, 50% isopropyl myristate (IPM), was assessed in two phase 2 trials conducted in North America. The first trial was a nonrandomized (proof of concept) trial without a comparator conducted in Winnipeg, Canada. The second trial, conducted in the United States, was an evaluator-blinded, randomized superiority trial comparing 50% IPM rinse with a positive control (RID; pyrethrin 0.33%, piperonyl butoxide 4%). The primary end points were to determine the safety and efficacy of 50% IPM as a pediculicide rinse. METHODS: Subjects meeting inclusion criteria were enrolled in the above-mentioned trials with efficacy end points 7 and 14 days post-treatment. Subjects were also evaluated on days 0, 7, 14, and 21 for the presence of erythema and edema using the Modified Draize Scale. Other comments associated with the safety evaluation (ie, pruritus) were collected. RESULTS: IPM was found to be effective in the proof of concept study and comparator trial using a positive control. IPM was also well tolerated, with minimal adverse events. All adverse events were mild, resolving by completion of the study. CONCLUSION: Data suggest that IPM is a safe and effective therapy for the treatment of head lice in children and adults. IPM's mechanical mechanism of action makes development of lice resistance unlikely.

Comparison of two partial least squares infrared spectrometric methods for the quality control of pediculosis lotions.

Two vibrational spectroscopy procedures have been developed and compared for the direct and simultaneous determination of piperonyl butoxide and tetramethrin, the active ingredients of alcoholic capillary lotions, for hair pediculosis diseases. Nine lotions, purchased from the Spanish market, were analyzed using both, attenuated total reflectance (ATR) and transmission FT-IR measurements, and based on the use of partial least squares (PLS) multivariate calibration. A reduced set of 15 matched standards (11 for calibration and 4 for validation) was employed using both measurement modes. The spectral wave number ranges between 1757 and 1712 cm(-1) was selected to determine tetramethrin by both, transmittance and reflectance measurements. For the analysis of piperonyl butoxide the 1513-1479 cm(-1) and 1576-1479 cm(-1) regions were selected for ATR and transmission measurements, respectively. Results found for commercial samples compared well with those obtained by a liquid chromatography reference method that evidenced the applicability of the proposed strategy for the analysis of commercial formulations.

[Investigation of pediculosis carried out as the special study module No. 74, a part of Ege University Medical Faculty's educational program]. / Ege Universitesi Tip Fakültesi egitim programi kapsamindaki 74 no'lu özel çalisma modülünde gerçeklestirilen pediculosis taramasi.

In this study, in the program of the special study module No: 74, 68 students, who attended the Izmir Konak Yüzbasi Serafettin Primary School were examined for Pediculus humanus capitis in March 2005. Twenty female students had pediculosis capitis, but no male students were infested. The infestation rate in the girls was 55.5%. Positive cases were treated and 35.0% were found to be cured during a control performed one week later.

Changes to oxfendazole chiral kinetics and anthelmintic efficacy induced by piperonyl butoxide in horses.

REASONS FOR PERFORMING THE STUDY: The study of novel pharmacological strategies to control parasitism in horses is required since many parasite species have developed resistance to anthelmintic drugs. OBJECTIVES: To evaluate the effects of piperonyl butoxide (PB) (a metabolic inhibitor) on the plasma availability and enantiomeric behaviour of oxfendazole (OFZ) given orally to horses, and to compare the clinical efficacy of OFZ given either alone or co-administered with PB in naturally parasitised horses. METHODS: Fifteen naturally parasitised crossbred male ponies were allocated into 3 groups (n = 5) and treated orally as follows: Group I (control) received distilled water as placebo; Group II was dosed with OFZ (10 mg/kg bwt); and Group III was treated with OFZ (10 mg/kg bwt) co-administered with PB (63 mg/kg bwt). Jugular blood samples were obtained over 120 h post treatment. Three weeks after treatments, all experimental horses were subjected to euthanasia. RESULTS: The observed maximum plasma concentration (Cmax) and area under the concentration vs. time curve (AUC) values for OFZ increased 3- and 5-fold, respectively, in the presence of PB. The plasma concentration profiles of fenbendazole (FBZ), a metabolite generated from OFZ, were significantly lower after the treatment with OFZ alone (AUC = 0.8 microg x h/ml) compared to those obtained after the OFZ + PB treatment (AUC = 2.7 microg x h/ml). The enhanced pharmacokinetic profiles correlated with increased anthelmintic efficacy. The combination OFZ + PB showed 100% efficacy against mature nematode parasites. The efficacy against cyathostome L3 larvae increased from 94% (Group II) to 98.7% (Group III). Consistently, the number of L4 larvae recovered from OFZ + PB treated horses (Group III) (n = 146) was significantly lower (P<0.05) than that recovered from Group II (n = 1397). CONCLUSIONS: The use of PB as a metabolic inhibitor may be useful to enhance OFZ activity against mature and migrating larvae of different parasite species in horses. POTENTIAL RELEVANCE: Metabolic inhibitors may be used to enhance the activity of benzimidazole anthelmintics and extend the effective lifespan of benzimidazole drugs in the face of increasing resistance.

The in vivo pediculicidal efficacy of a natural remedy.

BACKGROUND: Head louse infestations are prevalent worldwide. Over the past 20-25 years, 15-20% of all children in Israel between 4 and 13 years of age have been infested with head lice. This is mainly due to the existence of ineffective pediculicides on the market. OBJECTIVE: To examine the pediculicidal efficacy and safety of a natural remedy ("Chick-Chack") and to compare it in an open clinical study with a known pesticide spray. METHODS: The natural remedy, which contains coconut oil, anise oil and ylang ylang oil, was applied to the hair of infested children three times at 5 day intervals. Each treatment lasted for 15 minutes. The control pediculicide was a spray formulation containing permethrin, malathion, piperonyl butoxide, isododecane and propellant gas, which was applied twice for 10 minutes with a 10 day interval between applications. RESULTS: Of 940 children, aged 6-14 years, from six schools in Jerusalem who were examined for head louse infestation, 199 (21.2%) were infested with lice and eggs, while 164 (17.4%) were infested only with nits. Altogether, 119 children were randomly treated with either the natural remedy or the control product. Treatment was successful with the natural remedy in 60 children (92.3%) and with the control pediculicide in 59 children (92.2%). There were no significant side effects associated with either formulation. CONCLUSIONS: The natural remedy was very effective in controlling louse infestations under clinical conditions and caused no serious side effects.

Scabies and pediculosis pubis: an update of treatment regimens and general review.

The ectoparasites scabies and pediculosis pubis are common causes of skin rash and pruritus worldwide. They are transmitted primarily by person-to-person spread and are generally associated with low morbidity. The preferred treatment for scabies has generally been topical agents such as lindane and permethrin. Recently, ivermectin has demonstrated good efficacy in the treatment of scabies, and it may be of particular use in institutional outbreaks and in communities in which scabies is endemic. Combination treatment with topical agents and oral ivermectin may be necessary for crusted scabies. Treatment of pediculosis pubis is best accomplished with topical permethrin, lindane, or pyrethrins with piperonyl butoxide. Although resistance to these topical agents has been reported in head lice, decreased efficacy in the treatment of pediculosis pubis has not been reported.

A case of pubic lice resistant to pyrethrins.

BACKGROUND: Effective therapeutic protocols for the treatment of pubic lice include application of approved insecticidal products to all body and scalp hair, retreatment at seven days, and use of mechanical removal of lice and eggs. OBJECTIVE: We report here infection with pubic lice in a 43 year old male in Australia which failed to be eradicated by adequate therapy with a pyrethrin and piperonyl butoxide product. DISCUSSION: Pubic lice collected from the case survived after exposure to the same product in vitro. The infestation was cured by use of 5% permethrin. This appears to be the first report of Pthirus pubis resistant to insecticides, in this case pyrethrins and their synergist, piperonyl butoxide.

Clinical evidence of lice resistance to over-the-counter products.

BACKGROUND: Over-the-counter insecticidal solutions continue to be the mainstream treatment for most cases of head lice. Recorded insecticidal activity 15 years ago was at 100%, with ovicidal kill at 80%. Recently scattered accounts of possible resistance have surfaced. OBJECTIVE: This article is to document the general consensus that head lice are becoming resistant to standard over-the-counter therapies. METHODS: Direct testing of lethality of adult lice with permethrin and pyrethroid was assessed. RESULTS: Present over-the-counter products proved to be successful in only 9 of 32 head lice tested (28% insecticidal activity). CONCLUSIONS: Our series of cases further documents that over-the-counter head lice preparations no longer achieve high levels of insecticidal activity, suggesting increased resistance to these insecticides.

Cypermethrin pour-on synergized with piperonyl butoxide: effects on Haematobia irritans (Diptera: Muscidae) natural populations resistant to cypermethrin.

Development of pyrethroid resistance in Haematobia irritans in Santa Fe province, Argentina, resulted in an increased use of pyrethroid insecticides, probably due to lack of suitable alternative treatments. We explored the efficacy of mixtures of cypermethrin and piperonyl butoxide (PBO) against pyrethroid-resistant H. irritans. Groups of 25 Holstein cows each, naturally infested with cypermethrin resistant H. irritans were assigned to treated or control groups in April, September, October and December 1997. Cattle in treated groups were medicated with pour-on oil formulations of 5% cypermethrin (dose = 4 mg per kg of body weight) with 5% or 10% PBO in April, and with a mixture containing 5% of both components thereafter. Efficacy was tested for 21 days after treatment. A treatment of 5% cypermethrin pour-on without PBO was evaluated in October 1997. Samples of horn flies were obtained before September, October and December treatments and exposed for 2 h to filter papers impregnated with different cypermethrin concentrations to determine the 50% lethal concentration (LC50). No difference in efficacy was found between cypermethrin pour-on formulations with 5% or 10% of PBO (more than 94% efficacy on day 21 after treatment). Efficacy of 5 % cypermethrin-5% PBO mixture decreased rapidly in the successive treatments (less than 40% efficacy was observed on day 21 after the December treatment), and the period after treatment with an efficacy higher than 95% was 14 days for the treatment carried out in April, 10 days in September; 7 days for the treatment performed in October and 4 days for the December treatment. The LC50 of cypermethrin was 36.6 microg per cm2 in September and increased to 116.6 and 226.1 microg per cm2 in October and December, respectively. It is concluded that the addition of PBO to cypermethrin did not provide a treatment that would give a long term control of pyrethroid resistant-horn flies.

What's eating you? Pediculus humanus (head louse and body louse).

Head lice remain a common problem worldwide. As resistance to available therapeutic agents can emerge rapidly, there is a need for continued research to find new and better agents. Until better agents are available, clinicians may find that rotational therapy, using different agents, may help to slow the emergence of resistance. Physical modalities, such as mechanical nit and louse removal and occlusive agents to asphyxiate the lice, should not be ignored, especially in light of our limited therapeutic armamentarium. All therapeutic agents are doomed to failure if infestation is allowed to recur. Classmates, playmates, and family members of infested children should be inspected for head lice. Efforts should be directed at fomite control and nit removal. Louse infestation must be addressed as a community-wide problem. Body lice remain important vectors of disease. War, natural disaster, and poverty favor the spread of body lice. As we work to solve these seemingly eternal problems, we must develop better agents to treat infestation and prevent the spread of body lice.

Efficacy against sheep lice (Bovicola ovis) and fleece wetting of six shower dip preparations.

The relative efficacy of 6 shower dip chemicals most frequently used for the treatment of sheep lice (Bovicola ovis) in Western Australia was examined. Groups of 20 sheep infested with lice were treated with products containing either alphamethrin, cyhalothrin, diazinon or diazinon plus piperonyl butoxide and rotenone, formulated as emulsifiable concentrates, and with products containing either coumaphos or magnesium fluorosilicate, formulated as wettable powders. All treatments were applied through a shower dip (Sunbeam model SSD). Inspections for lice were conducted until 9 months after dipping. No lice were found on sheep treated with the 4 emulsifiable concentrate products. In contrast, treatment with the wettable powders, which contained either coumaphos or magnesium fluorosilicate as the active ingredient, did not eradicate the lice infestations. The degree to which the fleece was wetted was assessed 20 minutes after dipping and showed that the wettable powder dips penetrated the fleece less than the emulsifiable concentrate dips. Less fluid was retained by wool staples in an in-vitro test when dip wash was made with the wettable powders. It was concluded that the degree of wetting attained at dipping was an important factor in achieving eradication of sheep lice.