O-T-C products for the control of stinging and biting insects.
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Humans↗
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Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C).
Previously, we reported that two distinct in vitro tumor cell models of hypoxia (Models A and B) are hypersensitive to glycolytic inhibitors such as 2-deoxy-D-glucose (2-DG) and oxamate [Liu et al., Biochemistry 2001;40:5542-7]. Model A consists of osteosarcoma cells (143B) treated with agents that interfere with mitochondrial oxidative phosphorylation (OxPhos), and Model B represents rho(0) cells, a variant derived from 143B cells, which, due to their deficiency in mitochondrial DNA, cannot perform OxPhos. Extending these studies, we report here on Model C, which is composed of 143B cells grown under various levels of external O(2) (0, 0.1, 0.5, 1, 5, 10, and 21%). At the lower levels of O(2) that we tested, 143B cells were hypersensitive to 2-DG and oxamate when compared with cells grown at a normal level of O(2). In contrast, 143B cells under hypoxic or aerobic conditions showed equal sensitivity to a standard chemotherapeutic agent, vinblastine. Furthermore, when treated under reduced O(2) amounts, rho(0) cells displayed no hypersensitivity to 2-DG and, in fact, were slightly more resistant than under aerobic conditions. At 0-5% O(2) levels, untreated 143B cells displayed reduced growth and elevated lactic acid levels, while rho(0) cell growth remained unaffected except at 0% O(2) where growth was inhibited by 19%. The results with Model C are in agreement with our previous data using Models A and B, and extend these studies by illustrating that within a wide range of hypoxia the growth of tumor cells is retarded and that these slow-growing cells become hypersensitized to glycolytic inhibitors. Taken together with Models A and B, the data with Model C support our hypothesis that the hypoxic environment of slow-growing cells found in the inner core of solid tumors renders them amenable to selective targeting with glycolytic inhibitors.
Antimetabolites↗
Comparative chemical attributes of native North American hop, Humulus lupulus var. lupuloides E. Small.
The genetic diversity of 159 representative genotypes of native hop (Humulus lupulus var. lupuloides E. Small, Cannabaceae) from 34 selected populations was assessed by relative magnitudes and ranges of alpha acids (AA), beta acids (BA), and the cohumulone (CoH) component of alpha acids, with reference to temporal changes between 1989-1990 and 2001, and to the same attributes in American and European hop cultivars, principally H. lupulus var. lupulus L. Chemical profiles of these genotypes were generated by high pressure liquid chromatography (HPLC) of methanol extracts from their processed samples (cones). The alpha ratio (AR, alpha acids / alpha+beta acids) measured the degree to which alpha acids predominated in cone extracts. Synchronous ranges of AR and CoH were also selected for graphic portrayals of native hop genotypic diversity. Cones sampled and analyzed from eight populations that were accessible in both 1989 and 2001 were distinct in chemical attributes, indicating a succession of genotypes, and suggesting temporal cycling of H. lupulus var.lupuloides germplasm. The principal distinctions between the two sub-species were a markedly higher proportion of CoH (38-88% vs. 19-41%) in alpha acids of H. l. var. lupuloides, and generally higher concentrations of AA in cultivars of both American and European commercial hop cultivars, predominantly H. lupulus var. lupulus. All of the 159 native hop genotypes also contained detectable levels of xanthohumol and xanthogalenol, prenylflavonoids recently reported to have mammalian anti-cancer activity. Some native genotypes had previously exhibited natural repellence of insect and mite pests; thus H. lupulus var. lupuloides germplasm offers a diverse resource of underutilized and yet undefined biochemicals.
Carboxylic Acids↗
Studies in vitro on the relative efficacy of current acaricides for Sarcoptes scabiei var. hominis.
Resistance of Sarcoptes scabiei to various topical therapies has been described, but clinical assessment of treatment failure is problematic and in-vitro assays are generally not available. We describe a simple in-vitro analysis used to evaluate the relative efficacy of a range of topical, oral, and herbal treatments available in Australia for the treatment of scabies. S. scabiei var. hominis mites were collected from skin scrapings obtained from 7 crusted scabies patients over a period of 2 years (1997 and 1998). Larvae, nymphal instars, and adult mites were tested within 3 h of collection and continuously exposed to selected commercially available treatment products until death, with the elapsed time recorded. Neem was the only product to show little acaricidal activity. Survival curves indicated that, of the other agents, 5% permethrin (Lyclear) had the slowest killing time, with 35% of mites still alive after 3 h, and 4% still alive after 18-22 h of constant exposure. In contrast, no mites were alive after 3 h exposure to 25% benzyl benzoate (Ascabiol), 1% lindane (Quellada), 5% tea tree oil and 100-8000 ng/g of ivermectin (Equimec). Despite the slower killing time with 5% permethrin, there was no evidence of any mite tolerance in vivo or treatment failure in any patients or contact cases.
Animals↗
Schistosomiasis prophylaxis in vivo using N,N-diethyl-m-toluamide (DEET).
Topical N,N-Diethyl-m-toluamide (DEET) was studied as a schistosomiasis prophylactic in vivo for the use of individuals with limited exposure. Fifteen subjects, on a 3-week expedition to Lake Malawi in September 2001, applied 50% DEET to their skin after exposure to lake water. No subjects developed evidence of a new infection at 3-month follow-up.
Administration, Cutaneous↗
Drugs and personal care products as ubiquitous pollutants: occurrence and distribution of clofibric acid, caffeine and DEET in the North Sea.
An analytical method is presented, which allows the simultaneous extraction of neutral and acidic compounds from 20-L seawater samples at ambient pH (approximately 8.3). It is based on a solid-phase extraction by means of a polystyrene-divinylbenzene sorbent and gas chromatographic-mass spectrometric detection, and provides detection limits in the lower pg/L range. The method was applied to the screening of samples from different North Sea areas for clofibric acid, diclofenac, ibuprofen, ketoprofen, propyphenazone, caffeine and N,N-diethyl-3-toluamide (DEET). Whereas clofibric acid, caffeine and DEET showed to be present throughout the North Sea in concentrations of up to 1.3, 16 and 1.1 ng/L, respectively, propyphenazone could only be detected after further clean-up. Diclofenac and ibuprofen were found in the estuary of the river Elbe (6.2 and 0.6 ng/L, respectively) but in none of the marine samples. Ketoprofen was below the detection limit in all samples.
Caffeine↗
Control of arthropods of medical and veterinary importance.
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Aedes↗
The effects of pyridostigmine bromide, permethrin, and DEET alone, or in combination, on fixed-ratio and fixed-interval behavior in male and female rats.
Concurrent exposure to pyridostigmine bromide (PB), permethrin (PERM) and/or N,N-diethyl-m-toluamide (DEET) may have contributed to the development of a syndrome that appears to have afflicted military personnel who served during the Gulf War. The present experiment sought to evaluate the behavioral effects of these compounds alone, or in various combinations, in male and female rats. Subjects were exposed to a multiple fixed-ratio (FR) 50, fixed-interval (FI) 2-min schedule of reinforcement. PB dose-dependently decreased FR and FI response rates. FR responding was disrupted by lower doses and there were no differences between the sexes. PERM vehicle administration decreased response rates maintained by both schedules of reinforcement; this was offset by an increase in response rate after the administration of the intermediate dose of PERM. The highest dose of PERM decreased both FR and FI response rates. FR rates in male rats were more disrupted than those in female rats. Only the highest dose of DEET decreased FR and FI response rates in male and female rats. FR rates were more disrupted in female rats than in male rats. Synergistic effects were only observed when FI response rates decreased in male rats upon exposure to half the low dose of PB with half the low dose of PERM or half the low dose of PB with half the low dose of DEET. The results of this experiment thus show that small doses of PB, PERM and DEET disrupt well-established, schedule-controlled behavior in male and female rats in a schedule- and gender-dependent manner; schedule-dependent and gender-dependent synergistic effects were also observed. The mechanism by which the compounds exert these behavioral effects remains to be determined.
Animals↗
Pyridostigmine bromide alters locomotion and thigmotaxis of rats: gender effects.
Male rats and female rats in the proestrous and metestrous stages of estrus were tested to determine the effects of pyridostigmine bromide on locomotion rate and thigmotactic response using doses of 3.0, 10.0, and 30.0 mg/kg. Thirty minutes after administration of the pyridostigmine bromide the rats were videorecorded for 2 h in a 1 m2 open-field arena. The rats' activities were analyzed for the drug's effect on speed throughout the 2 h and during six 20-min segments. Also, the times that the rats were observed moving through the central 50% of the arena were determined. Locomotion rates decreased significantly, and thigmotaxses increased significantly in all groups of rats as a dose response to pyridostigmine bromide. Habituation occurred over 2 h for both responses, primarily during the first 40 min. Female rats were more affected than males, but metestrous and proestrous females did not differ significantly in their responses. At the 30 mg/kg the effect was persistent throughout the test period. Proestrous females dosed at 30 mg/kg had much higher pyridostigmine bromide serum levels than metestrous females and males.
Animals↗
Plant-based malaria control: research initiative on traditional antimalarial methods.
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Antimalarials↗
New approaches to the treatment of canine demodicosis.
Topical amitraz is the only approved treatment for CGD; however, it is not always effective or well tolerated. Extra-label use of amitraz, milbemycin oxime, ivermectin, and moxidectin may be effective therapeutical alternatives for dogs with resistant CGD or dogs that have an intolerance to the licensed amitraz protocol. It appears that oral administration of milbemycin oxime (1-2 mg/kg), ivermectin (400-600 micrograms/kg), and moxidectin (400 micrograms/kg) daily is a practical therapeutical alternative and would provide similar cure rates. Nevertheless, milbemycin oxime is expensive, ivermectin is potentially more toxic, and only limited information is available on moxidectin. The average treatment duration with these new regimens is 4 months, with an expected range of 3 to 10 months. Treatment should be administered daily for a minimum of 3 months and for at least 1 month after a series of negative skin scrapings. For chronic cases or cases that take a relatively long time to respond to therapy, 2 to 3 months of treatment beyond negative scrapings may be more appropriate. Dogs with CGD always approach clinical normalcy weeks to months before negative skin scrapings are obtained. All dogs respond at their own rate; as long as the skin scrapings at each visit show fewer mites, the current therapy should be continued for an additional month. If the mite count starts to increase, this may suggest that the treatment protocol is not being followed or it may be that the therapy chosen was suboptimally effective. Although CGD is still a disease that is not easily treated, the prognosis for dogs with this disorder has dramatically improved in the past few years. It must be remembered, however, that the treatment alternatives for CGD described above are not approved and should not be used unless the approved therapeutical regimen has failed.
Animals↗
[Prophylaxis of malaria].
The prevention of malaria is based on chemoprophylaxis and protection against the vector. Nocturnal mosquito bites can be avoided by individual and collective measures, while chemoprophylaxis involves the use of various agents according to the place and duration of stay. Three endemic zones can be defined on the basis of chemoresistance. Chloroquine, proguanil and mefloquine are the three drugs used in this setting, the latter being contraindicated for pregnant women and children. Travellers making long stays in areas of low-level chemoresistance and short stays in areas of high-level resistance and for whom mefloquine is contraindicated are advised to take antimalarial drugs at the first signs of potentially malarial fever when medical care is unavailable. Quinine, halofantrine and mefloquine are used for the curative treatment of malaria in areas of chloroquine resistance.
Africa↗
In vitro acaricidal effect of plant extract of neem seed oil (Azadirachta indica) on egg, immature, and adult stages of Hyalomma anatolicum excavatum (Ixodoidea: Ixodidae).
Effects of the plant extract of neem seed (Azadirachta indica) on eggs, immature, and adult stages of Hyalomma anatolicum excavatum was studied at concentrations of 1.6, 3.2, 6.4, and 12.8%. The extract was found to have a significant effect on the hatching rate of eggs. It significantly increased the hatching rate during the first 7 days post-treatment (DPT) giving incompletely developed and dead larvae; however, it cause hatching failure at DPT 15. Neem Azal F induced a significant increased in mortality rates of newly hatched larvae, unfed larvae, and unfed adults reaching 100% on 15th, 3rd, and 15th DPT, respectively. The mortality rates increased with the extract concentrations. Although, it had no significant effect on the moulting rates of fed nymphs, it caused malformation or deformities in 4% of adults moulted. It was concluded that the concentration of Neem Azal F which may be used for commercial control of this tick species were 1.6 and 3.2%.
Animals↗
Increased 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA damage in rat urine following a single dermal dose of DEET (N, N-diethyl-m-toluamide), and permethrin, alone and in combination.
Levels of the biomarker of DNA oxidative damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) in rat urine following dermal exposure to DEET (N,N-diethyl-m-toluamide) and permethrin, alone and in combination have been determined. A group of five rats for each time point were treated with a single dermal dose of 400 mg/kg of DEET, 1.3 mg/kg of permethrin or their combination. Urine samples were collected 2,4,8,16,24,48, and 72 h following application. Control urine samples of rats treated with ethanol were also collected at the same time intervals. Solid phase extraction coupled with high performance liquid chromatography (HPLC) with UV detection at 254 nm was used for determination of 2'-deoxyguanosine, and (8-OHdG). The limits of detection (LOD) were 0.5 ng of both 2'-deoxyguanosine and 8-OHdG. Their average percentage recoveries from urine samples were between 70-85%. A single dermal dose of DEET or in combination with permethrin significantly induced levels of (8-OHdG) that are excreted in the urine over the time course of the study compared to control urine samples. Permethrin did not cause significant increase in the amount of 8-OHdG in the urine. Levels of 8-OHdG in urine excreted at 24 h were 1009+/-342, 1701+/-321, 1140+/-316, and 1897+/-231 ng following treatment with ethanol, DEET, permethrin, and DEET+permethrin, respectively. The results indicate that dermal administration of DEET could generate free radical species hence cause DNA oxidative damage in rats.
8-Hydroxy-2'-Deoxyguanosine↗
Induction of urinary excretion of 3-nitrotyrosine, a marker of oxidative stress, following administration of pyridostigmine bromide, DEET (N,N-diethyl-m-toluamide) and permethrin, alone and in combination in rats.
In this study, we determined levels of 3-nitrotyrosine in rat urine following administration of a single oral dose of 13 mg/kg pyridostigmine bromide (PB) (3-dimethylaminocarbonyloxy-N-methylpyridinum bromide), a single dermal dose of 400 mg/kg N,N-diethyl-m-toluamide (DEET) and a single dermal dose of 1.3 mg/kg permethrin, alone and in combination. Urine samples were collected from five treated and five control rats at 4, 8, 16, 24, 48, and 72 h following dosing. Solid-phase extraction coupled with high-performance liquid chromatography with ultraviolet detection at 274 nm was used for the determination of tyrosine and 3-nitrotyrosine. A single oral dose of PB and a single dermal dose of DEET or their combination significantly (P<0.05) increased levels of 3-nitrotyrosine starting 24 h after dosing compared with control urine samples. The maximum increase of 3-nitroytyrosine was detected 48 h after combined administration of PB and DEET. The ratio of 3-nitrotyrosine to tyrosine in urine excreted 48 h after dosing was 0.19+/-0.04, 0.20+/-0.05, 0.28+/-0.03, 0.32+/-0.04, 0.19+/-0.05, 0.42+/-0.04, 0.27+/-0.03, 0.36+/-0.04, and 0.48+/-0.04 following administration of water, ethanol, PB, DEET, permethrin, PB+DEET, PB+permethrin, DEET+permethrin, and PB+DEET+permethrin, respectively. The results indicate that an oral dose of PB and a dermal administration of DEET, alone and in combination, could generate free radical species, and thus increase levels of 3-nitrotyrosine in rat urine. Induction of 3-nitrotyrosine, a marker of oxidative stress, following exposure to these compounds could be significant in understanding the proposed enhanced toxicity following combined exposure to these compounds.
Administration, Oral↗
Gulf War related exposure factors influencing topical absorption of 14C-permethrin.
Topical exposure to permethrin has often been implicated as a mitigating factor in the illnesses reported in Gulf War veterans. These studies were designed to assess the effect of co-exposure to low level sulfur mustard, JP-8 jet fuel, N,N-diethyl-m-toluamide (DEET) and fabric occlusion on the percutaneous absorption and skin disposition of topically applied 14C-permethrin (40 microg/cm(2)) in the isolated perfused porcine skin flap (IPPSF) model. Extent of dermal absorption in vehicle controls in the IPPSF was comparable to literature values for humans. These studies demonstrated a two-fold increased 14C-permethrin percutaneous absorption and almost three-fold increased penetration when JP-8 was present, compared to a one-third decreased permethrin flux in the presence of sulfur mustard. Complete occlusion slightly increased 14C-permethrin absorption, while occlusion with fabric showed no significant effect. A previously noted effect of DEET to inhibit permethrin absorption was still seen in the presence of sulfur mustard exposure. These studies suggest that co-exposure to JP-8 or sulfur mustard may modulate transdermal flux of 14C-permethrin. However, the JP-8 increase in absorption and penetration was less than the five-fold increase previously seen with arterial infusion of pyridostigmine bromide and diisopropylfluorophosphate in the IPPSF. The toxicologic significance of this moderate increase in permethrin absorption remains unclear.
Animals↗