Cellular and molecular mechanisms of DEET toxicity and disease-carrying insect vectors: a review.

BACKGROUND: Several insects such as mosquitoes, flies, ticks, fleas, lice, and mites are known to serve as vectors for a vast number of pathogens. Many such vectors are hematophagous, and therefore introduce pathogens directly into the host's bloodstream. Importantly, the capacity of these vectors to spread disease can lead to serious global health crises. Furthermore, crop damage can be exacerbated by pathogen infection and increased insect foraging due to recent global warming. METHODS: Our study categorized insect-associated damage into three groups: animal infection, plant infection, and direct crop damage due to insect foraging. To manage these problems, insect repellents and pesticides have been developed, among which DEET is the most broadly used and studied pest control agent. This review discusses the mode of action and possible mechanisms of DEET action, including olfactory and gustatory mechanisms and central nervous system impairment. CONCLUSION: To protect humans from malaria, yellow fever, dengue fever, zika, and filariasis, as well as to reduce economic losses associated with crop damage, considerably more efforts are needed to characterize the interactions between insects and insect repellents/pesticides to develop more potent pest control agents.

Rocky Mountain Spotted Fever.

The tick-borne disease Rocky Mountain spotted fever (RMSF) can have deadly outcomes unless treated appropriately, yet nonspecific flu-like symptoms complicate diagnosis. Occupational health nurses must have a high index of suspicion with symptomatic workers and recognize that recent recreational or occupational activities with potential tick exposure may suggest RMSF.

A review of recommendations on the safe and effective use of topical mosquito repellents.

Mosquito-borne disease is an annual problem in Australia, with endemic pathogens such as Ross River virus infecting thousands of people each year. The recent emergence of Zika virus in South America and the Pacific, together with ongoing outbreaks of dengue viruses in Southeast Asia, generated great community interest in the most effective strategies to avoid mosquito bites. Large-scale mosquito control programs are not common in Australia and are limited in New South Wales (NSW). The use of topical insect repellents is a key recommendation by health authorities to prevent mosquito-borne disease. All products sold in Australia purporting to repel mosquitoes must be registered with the Australian Pesticides and Veterinary Medicines Authority. Despite around 100 commercial products registered as repelling mosquitoes, there are relatively few active ingredients used across these formulations. The most common are diethyltoluamide (DEET), picaridin, p-menthane-3,8-diol (PMD) and a range of plant-derived products (e.g. melaleuca, eucalyptus, citronella oils). Research has shown that each of these active ingredients varies in the duration of protection provided against biting mosquitoes. Recommendations by health authorities are informed by this research, but inconsistencies between recommendations and available repellent formulations and their concentration of active ingredients can cause confusion in the community. There are conflicts between the data resulting from scholarly research, marketing promotion by manufacturers and recommendations provided by overseas health authorities. A review was undertaken of NSW Health's current recommendations on choosing and using insect repellents, taking into consideration recent research and currently registered topical repellents.

Insect Repellants During Pregnancy in the Era of the Zika Virus.

Health care providers must be equipped to provide appropriate advice to reproductive-aged patients for protection against the potentially devastating consequences of prenatal Zika virus exposure. The goal of this commentary is to summarize what is known about the safety and toxicity of N,N-diethyl-meta-toluamide (DEET) as a topical insect repellant and the pyrethroid permethrin for treatment of fabric, endorsed in the fight against Zika virus. Reviews assessing the safety and toxicity of DEET conducted by the U.S. Environmental Protection Agency and the Canadian Pest Management Regulatory Agency conclude that DEET has low acute toxicity and does not appear to pose a significant health concern to humans when used as directed. Some experimental animal and limited epidemiologic data suggest that prenatal pyrethroid exposure may adversely affect learning and behavior, but this level of evidence pales in comparison to the known risks of Zika virus to the fetal brain. The available evidence has led to the strong recommendation by the Centers for Disease Control and Prevention for use of these products by pregnant women as personal protection against mosquito bites in the fight against Zika virus infection. This message has been affirmed by our obstetrics and gynecology professional organizations. Because Zika virus is unlikely to be the last disease requiring vector control, those with environmental health expertise must continue to join with infectious disease specialists to communicate the potential vulnerability of our youngest (fetuses, infants, and young children) to vector-borne disease, both to the disease itself and to the strategies employed to mitigate the spread of such disease.

A cluster-randomized controlled trial to assess the effectiveness of using 15% DEET topical repellent with long-lasting insecticidal nets (LLINs) compared to a placebo lotion on malaria transmission.

BACKGROUND: Long-lasting insecticidal nets (LLINs) have limited effect on malaria transmitted outside of sleeping hours. Topical repellents have demonstrated reduction in the incidence of malaria transmitted in the early evening. This study assessed whether 15% DEET topical repellent used in combination with LLINs can prevent greater malaria transmission than placebo and LLINs, in rural Tanzania. METHODS: A cluster-randomized, placebo-controlled trial was conducted between July 2009 and August 2010 in a rural Tanzanian village. Sample size calculation determined that 10 clusters of 47 households with five people/household were needed to observe a 24% treatment effect at the two-tailed 5% significance level, with 90% power, assuming a baseline malaria incidence of one case/person/year. Ten clusters each were randomly assigned to repellent and control groups by lottery. A total of 4,426 individuals older than six months were enrolled. All households in the village were provided with an LLIN per sleeping space. Repellent and placebo lotion was replaced monthly. The main outcome was rapid diagnostic test (RDT)-confirmed malaria measured by passive case detection (PCD). Incidence rate ratios were estimated from a Poisson model, with adjustment for potential confounders, determined a priori. According-to-protocol approach was used for all primary analyses. RESULTS: The placebo group comprised 1972.3 person-years with 68.29 (95% C.I 37.05-99.53) malaria cases/1,000 person-years. The repellent group comprised 1,952.8 person-years with 60.45 (95% C.I 48.30-72.60) cases/1,000 person-years, demonstrating a non-significant 11.44% reduction in malaria incidence rate in this group, (Wilcoxon rank sum z=0.529, p=0.596). Principal components analysis (PCA) of the socio-economic status (SES) of the two groups demonstrated that the control group had a higher SES (Pearson's chi square=13.38, p=0.004). CONCLUSIONS: Lack of an intervention effect was likely a result of lack of statistical power, poor capture of malaria events or bias caused by imbalance in the SES of the two groups. Low malaria transmission during the study period could have masked the intervention effect and a larger study size was needed to increase discriminatory power. Alternatively, topical repellents may have no impact on malaria transmission in this scenario. Design and implementation of repellent intervention studies is discussed. TRIAL REGISTRATION: The trial was registered ISRCTN92202008--http://www.controlled-trials.com/ISRCTN92202008.

Química Farmacéutica de las Acilaminometilpiridinas / Pharmaceutical Chemistry of Acylaminomethylpyridines

Se han sintetizado una nueva familia de depresores del Sistema Nervioso Central, basado en un sistema denominado actualmente la 'utilización de fragmentos'. A uno de los fármacos obtenidos por este procedimiento la OMS le asignó el nombre de picobenzida. Al tratarse de una benzamida sustituida se prepararon análogos modificando los sustituyentes del anillo aromático y se llevó a cabo un estudio QSAR de la serie, que condujo a la optimización de la misma. Un ensayo para modificar el anillo de piridina condujo a una nueva reacción de dimerización para esta clase de compuestos (AU)

A new family of central nervous system depressants has been synthesized, applying the methodology now known as the 'use of fragments'. One of the drugs produced by this process was assigned the name picobencide by WHO. Being a substituted benzamide, analogues were prepared modifying the substituents of the aromatic ring. A QSAR study was carried out which led to the optimization of the series. A test to modify the pyridine ring led to a new dimerization reaction of this kind of compounds (AU)

[Prevention with repellent in children]. / Prévention par insectifuge chez l'enfant.

Use of topical insect repellent is an important component in prophylaxis of arthropod bite vector borne diseases. Topical insect repellent are used in a three part management regimen, along with impregnated clothing and mosquito netting. Parental training for efficacious and secure use of repellents for their children is essential part of a successful strategy to combat Lyme borreliosis, dengue fever, Chikungunya, West Nile virus infection and malaria, amongst children, according to local epidemiological risks. Rational repellent prescription for a child must take into account age, active substance concentration, topical substance tolerance, nature and surface of the skin to protect, number of daily applications, and the length of use in a benefit-risk ratio assessment perspective. The 4 currently repellents recommended by Whopes (Who) for their long lasting efficacy and patient tolerance are: 1) Citriodiol (PMD), 2) DEET, 3) Icaridine (KB3023), and 4) IR3535. In field trials the minimum required concentration of each four of these agents to be effective for 3 hours against most arthropods is 20% (in cream, roll-on or spray vehicle). Described side effects of these agents are mild, being limited to local irritative dermatitis and allergy. The risk of severe side effects has been related to DEET misused and neurotoxicity. The international recommendations concerning utilization of topical repellent amongst children for prophylaxis of arthropod borne diseases is concerning short term usage (several weeks). But the use of repellent is sub chronic or chronic amongst the majority of children living in subtropical regions where these vector borne diseases are endemic. And toxicity of topical repellent when used sub-chronically and chronically is not well studied in pediatric age groups. Taking into account these considerations, the current recommendations of the French Group of Tropical Paediatrics are to teach the parents of children who live in arthropod vector disease endemic regions to use topical insect repellent on their children with the recommended age related frequency in the following way: the use of topical repellent in infants above 6 months, once daily. Only in exceptional circumstances of severe arthropod exposure risk, their brief use in nursing infants as young as 2 months is acceptable, however with never more than 1 application daily. From ages 1 to 12 years, 2 applications daily may be safely used; 3 applications daily after 12 years old through adulthood.

Insect repellents and sunscreen: implications for personal protection strategies against mosquito-borne disease.

OBJECTIVE: To determine the protection times provided by insect repellent and sunscreen in combined formulations against biting mosquitoes. To determine if concurrent use of repellent and sunscreen influenced protection times. METHODS: Insect repellent containing comparable concentrations of N, N-diethyl-3-methylbenzamide (DEET) with and without sunscreen were tested on human skin to determine the mean protection time (MPT) against Aedes aegypti (L.) in the laboratory. Further trials were undertaken to determine the effect on MPT of sunscreen reapplication over repellent every two hours. RESULTS: There was no significant difference in the MPT provided by 80% DEET with (MPT+/-SE=770+/-54.8 minutes) and without (MPT+/-SE=830+/-20.2 minutes) sunscreen or 7.14% DEET with (MPT+/-SE =240+/-15.5 minutes) and 6.98% DEET without (MPT+/-SE =230+/-18.4 minutes) sunscreen. Reapplication of sunscreen resulted in a significantly lower MPT of a 17.0% DEET formulation when sunscreen was reapplied concurrently (MPT+/-SE=330+/-25.2 minutes), compared with DEET alone (MPT+/-SE =400+/-12.7 minutes). CONCLUSIONS: When combined in a single formulation with sunscreen, the MPT provided by both high and low concentrations of DEET is not reduced. However, if sunscreen is reapplied over insect repellent, protection times can be reduced significantly. IMPLICATIONS: In areas of endemic mosquito-borne disease, the reapplication of a low concentration repellent and sunscreen formulation may provide the most effective protection from biting mosquitoes while minimising the risk of overexposure to DEET.

Field trials on the efficacy of DEET-impregnated anklets, wristbands, shoulder, and pocket strips against mosquito vectors of disease.

A field trial was undertaken in order to determine the efficacy of DEET (N,N-diethyl-m-toluamide) impregnated anklets, wristbands, shoulder and pocket fabric strips against mosquito vectors of disease. The present study was conducted in the urban locality of Pondicherry, India. Human test subjects were exposed to natural populations of mosquitoes for a 12 h (18.00-06.00) night time period. The fabric strips (anklets, wristbands, shoulder, and pocket strips) were impregnated with DEET at two different concentrations of 1.5 mg/cm(2) and 2.0 mg/cm(2). The results clearly revealed that DEET-impregnated anklets, wristbands, shoulder and pocket fabric strips were found more effective against mosquitoes remarkably. The DEET-impregnated anklets, wristbands, shoulder and pocket fabric strips at a concentration of 2 mg/cm(2) provided 5 h complete protection against mosquitoes bites and the reduction of man-landing rate varied between 65.85 and 100%. However, DEET-impregnated fabric strips at a concentration of 1.5 mg/cm(2) provided 4 h complete protection against mosquito bites and the reduction of man-landing rate varied between 51.21 and 100%. The final results clearly demonstrate that repellent activity of DEET-impregnated anklets, wristbands, shoulder, and pocket strips were dose-dependent. Certainly, the DEET-impregnated fabric strips can be used as an effective potential personal protection measure in order to avoid those insects/mosquitoes that prefer to feed outdoors or those that feed in the early evening.

Factors associated with the use of protective measures against vector-borne diseases among troops deployed to Iraq and Afghanistan.

BACKGROUND AND METHODS: Vector-borne diseases are known threats to deployed troops. We performed a cross-sectional study of troops deployed to Southwest Asia between January 2005 and February 2007 to evaluate practices of personal protective measures and their relationship to self-report of Old World cutaneous leishmaniasis (CL), a marker of vector-borne disease threat. RESULTS: Regular or always N, N-diethyl-m-toluamide (DEET) use was low (2-5%). Associations for DEET use were command emphasis, branch of service, uniform treatment with permethrin, and duty station. Uniform treatment with permethrin was associated with branch of service, command emphasis, and use of DEET. We identified 22 cases of CL (incidence density of 1.8-3.7 per 100 person-years) with increased risk among Reserve/National Guard components, Air Force and Marine personnel. CONCLUSIONS: Commanders can influence the use of the military insect repellent system. Unit-based treatment of uniforms improves prevalence. CL incidence may be higher than previously reported.

Efficacy of topical permethrin as repellent against Aedes aegypti's bites.

Mosquitoes are the most important vectors of infectious diseases and their bites are related to several adverse skin reactions. Permethrin impregnated clothes are an efficient strategy against arthropods' bites; however, its topical efficacy as a repellent has not been well established. We studied the response to permethrin lotion 5 percent and N,N-Diethyl-meta-toluamide (DEET) spray 50 percent applied to the unprotected forearms of 10 volunteers. Each arm was exposed to 20 female mosquitoes of Aedes aegypti. We performed 71 bilateral comparative measurements evaluating the timing for the first bites. The average times for the arm without the product, with permethrin 5 percent, and with DEET 50 percent were: 7.9 seconds, 336.2 seconds and 7512.1 seconds. The results showed a significant difference between repellency times between either product and unprotected controls. In addition, there was a significant difference in time to first bite between permethrin and DEET treated arms (p<0.01). Permethrin affords some repellent activity against Aedes aegypti bites in this experimental setting. However, permethrin's profile of repellency was significantly inferior to that of DEET.

Insect repellents: historical perspectives and new developments.

Arthropod bites remain a major cause of patient morbidity. These bites can cause local or systemic effects that may be infectious or inflammatory in nature. Arthropods, notably insects and arachnids, are vectors of potentially serious ailments including malaria, West Nile virus, dengue, and Lyme disease. Measures to curtail the impact of insect bites are important in the worldwide public health effort to safely protect patients and prevent the spread of disease. The history of insect repellent (IR) lends insight into some of the current scientific strategies behind newer products. Active ingredients of currently available IRs include N,N-diethyl-3-methylbenzamide (DEET), botanicals, citronella, and, the newest agent, picaridin. Currently, the Environmental Protection Agency's registered IR ingredients approved for application to the skin include DEET, picaridin, MGK-326, MGK-264, IR3535, oil of citronella, and oil of lemon eucalyptus. DEET has reigned as the most efficacious and broadly used IR for the last 6 decades, with a strong safety record and excellent protection against ticks, mosquitoes, and other arthropods. Newer agents, like picaridin and natural products such as oil of lemon eucalyptus are becoming increasingly popular because of their low toxicity, comparable efficacy, and customer approval. Various characteristics and individual product advantages may lead physicians to recommend one agent over another.

A comparison of botanical and synthetic substances commonly used to prevent head lice (Pediculus humanus var. capitis) infestation.

BACKGROUND: Pediculosis, caused by head lice (Pediculidae: Pediculus humanus var. capitis), is experiencing a global resurgence, with the prevalence in primary schools averaging as high as 40% in some areas regardless of socioeconomic factors. Control efforts using chemical treatments are becoming increasingly ineffective, with insecticide resistance recorded in several countries. Prevention using repellents and oils would be useful if they limited transmission. Many commercially available substances reputedly have effective repellent qualities, but remain untested. METHODS: This study tested the preventative efficacy of N,N-diethyl-3-methylbenzamide (DEET) against several commercially available botanicals to clarify their value as transmission inhibitors, irritants, repellents, and antifeedants. RESULTS: The transfer of head lice to treated hairs was limited by the slippery nature of the oils rather than their repellent qualities. Irritancy was not important because lice proceeded despite being highly irritated, except in the case of coconut. Tea tree and peppermint caused the most repellence, and tea tree and lavender prevented some blood feeding on treated skin. Comparatively, tea tree oil was most efficacious, with DEET ranking equal second overall with coconut, peppermint, and a botanical mixture. CONCLUSIONS: Neither DEET nor any of the botanicals tested showed sufficient preventative efficacy to be endorsed.

Cream formulations protecting against cercarial dermatitis by Trichobilharzia.

Dermatitis caused by penetrating bird schistosome cercariae is an emerging global public health problem. Infections may be prevented by the use of topical formulations that inhibit cercarial skin penetration. We evaluated nine water resistant formulations by exposing treated arms of volunteers to Trichobilharzia szidati cercariae. Six formulations protected from cercarial invasion. However, after immersion of the treated skin in water (2 x 20 min), only two formulations offered full protection: (1) Safe Sea, a cream protecting against jelly fish, (2) niclosamide in water resistant sun protecting cream formulations at concentrations as low as 0.05%. In an in vitro system Safe Sea and a 0.1% niclosamide formulation caused a high damage rate in T. szidati (92% and 99% after 5 min; only niclosamide with lethal effect) but not in Schistosoma mansoni (1% and 72%; both formulations with lethal effect). However, a 1% niclosamide formulation damaged S. mansoni sufficiently (100% after 5 min) and might offer full penetration protection.

Laboratory determination of protection time in four chemical repellents against Anopheles stephensi.

In the present study we determined the Protection Time (PT) and Failure Time (FT) of the DMP lotion, which is synthesized and formulated in Iran and it was compared with other products such as MIP60 and Dimp31.7 lotions (commercial and current formulations of dimethyl phthalate) and trench pomade (a popular local repellent in Iran) against Anopheles stephensi Liston (main malaria vector in south of Iran) in laboratory condition. In this research which is an interventional and experimental study, the screen cage method was used to estimate PT and FT of repellents against An. stephensi. The following commercial formulations of chemical repellents were tested: Iranian DMP lotion (DMP60) (contains 60% dimethyl phthalate, 25% isopropyl alcohol, 5% twine 80 and 10% water), MIP60 and Dimp31.7 lotions contains 60 and 31.7% active ingredient of dimethyl phthalate and trench pomade (a combination of N,N-diethyl-m-toluamide (DEET) and DMP). Test was done on human volunteers. In this test some defined amount of repellents applied on human volunteer's forearm and then was inserted in cage against mosquitoes biting to determine PT and FT. According to the results of this research, the PT of Iranian DMP60 lotion against An. stephensi was determined about 274 min (SE = ++/-.04), which didn't have any significant difference with MIP60 and trench pomade, but it was significantly more than Dimp31.7. Furthermore the FT of DMP60 against An. stephensi was determined about 327 min (SE = +/-10.47), that in this case it had a significant deference with MIP60 lotion and trench pomade. The failure time of DMP60 was less than another two repellents. The Iranian DMP60 lotion can potentially compete with MIP60 and Dimp31.7, but to increase the FT rate, its formulation need to be improved.