Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m-toluamide (DEET).
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Chronic toxicity and/or oncogenicity studies were conducted in rats, mice, and dogs with the insect repellent DEET. DEET was mixed in the diet and administered to CD rats for two years at concentrations that corresponded to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400 mg/kg/day for females; to CD-1 mice for 18 months at dosage levels of 250, 500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each group consisted of 60 animals of each sex, and two concurrent independent control groups, each containing 60 animals/sex were included in each study. Each group in the dog study consisted of four male and four female dogs and one control group was included in the study. Treatment-related effects were observed at the highest dose level in all three studies. For rats, the effects included decreases in body weight and food consumption and an increase in serum cholesterol in females only. In mice, the effects observed were decreases in body weight and food consumption in both sexes. The effects observed in dogs included increased incidences of emesis and ptyalism, and levels of transient reduction in hemoglobin and hematocrit, increased alkaline phosphatase (males only), decreased cholesterol, and increased potassium. One male dog in the high-dose group also exhibited ataxia, tremors, abnormal head movements, and/or convulsions on several occasions during the study. The highest no-observed-effect levels (NO-ELs) for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day, respectively. No specific target organ toxicity or oncogenicity was observed in any of the studies. (+info)
Lyme disease: recognition, management, and prevention in the primary care setting.
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This activity is designed for practitioners who see patients with tick bites, Lyme disease, or suspected Lyme disease in their practice, whether or not the practitioner is in an endemic area for Lyme disease. GOAL: To help primary care practitioners recognize and treat Lyme disease and provide preventive counseling. OBJECTIVES: 1. Be familiar with the terminology used for the causative agent of Lyme disease, its tick vector and reservoirs in nature, and where the disease is endemic. 2. Know the features of the common, characteristic clinical forms of Lyme disease. 3. Appreciate the uses and limitations of laboratory testing for this infection. 4. Understand early antibiotic treatment of Lyme disease, the management of a tick bite, and preventive measures. (+info)
Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits.
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Although it is recognized that late preconditioning (PC) results from upregulation of cardioprotective genes, the specific transcription factor(s) that govern this genetic adaptation remains unknown. The aim of this study was to test the hypothesis that the development of late PC is mediated by nuclear factor-kappaB (NF-kappaB) and to elucidate the mechanisms that control the activation of NF-kappaB after an ischemic stimulus in vivo. A total of 152 chronically instrumented, conscious rabbits were used. A sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles, which elicits late PC, induced rapid activation of NF-kappaB, as evidenced by a marked increase in p65 content (+164%; Western immunoblotting) and NF-kappaB DNA binding activity (+306%; electrophoretic mobility shift assay) in nuclear extracts isolated 30 minutes after the last reperfusion. These changes were attenuated 2 hours after ischemic PC and resolved by 4 hours. Competition and supershift assays confirmed the specificity of the NF-kappaB DNA complex signals. The mobility of the NF-kappaB DNA complex was shifted by anti-p65 and anti-p50 antibodies but not by anti-c-Rel antibodies, indicating that the subunits of NF-kappaB involved in gene activation after ischemic PC consist of p65-p50 heterodimers. Pretreatment with the NF-kappaB inhibitor diethyldithiocarbamate (DDTC; 150 mg/kg IP 15 minutes before ischemic PC) completely blocked the nuclear translocation and increased DNA binding activity of NF-kappaB. The same dose of DDTC completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that NF-kappaB activation is essential for the development of this phenomenon in vivo. The ischemic PC-induced activation of NF-kappaB was also blocked by pretreatment with Nomega-nitro-L-arginine (L-NA), a nitric oxide synthase (NOS) inhibitor, N-2-mercaptopropionyl glycine (MPG), a reactive oxygen species (ROS) scavenger, chelerythrine, a protein kinase C (PKC) inhibitor, and lavendustin A, a tyrosine kinase inhibitor (all given at doses previously shown to block late PC), indicating that ischemic PC activates NF-kappaB via formation of NO and ROS and activation of PKC- and tyrosine kinase-dependent signaling pathways. A subcellular redistribution and increased DNA binding activity of NF-kappaB quantitatively similar to those induced by ischemic PC could be reproduced pharmacologically by giving the NO donor diethylenetriamine/NO (DETA/NO) (at a dose previously shown to elicit late PC), demonstrating that NO in itself can activate NF-kappaB in the heart. Taken together, these results provide direct evidence that activation of NF-kappaB is a critical step in the signal transduction pathway that underlies the development of the late phase of ischemic PC in conscious rabbits. The finding that four different pharmacological manipulations (L-NA, MPG, chelerythrine, and lavendustin A) produced similar inhibition of NF-kappaB suggests that this transcription factor is a common downstream pathway through which multiple signals elicited by ischemic stress (NO, ROS, PKC, tyrosine kinases) act to induce gene expression. To our knowledge, this is the first demonstration that NO can promote NF-kappaB activation in the heart, a finding that identifies a new biological function of NO and may have important implications for various pathophysiological conditions in which NO is involved and for nitrate therapy. (+info)
Gender-related efficacy difference to an extended duration formulation of topical N,N-diethyl-m-toluamide (DEET).
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A clinical trial (n = 120, 60 males and 60 females) was conducted to assess the efficacy of an extended duration tropical insect/arthropod repellent (EDTIAR) topical formulation of N,N-diethyl-m-toluamide (DEET). The amount of EDTIAR (mean +/- confidence interval), applied by participants in accordance with label directions, was not significantly different between females (3.66 +/- 0.32 mg/cm2) and males (3.45 +/- 0.33 mg/cm2). There also was no significant difference in the number of Anopheles stephensi mosquitoes biting the control arm of females or males at 0, 3, 6, 9, and 12 hr. While gender had no effect on feeding, the time of day did effect mosquito feeding with fewer mosquitoes feeding in the afternoon than in the morning or evening. The percent protective efficacy at 0, 3, 6, 9, and 12 hr was 100.0, 99.3, 92.8, 79.7 and 66.3 for females, and 100.0, 100.0, 97.6, 91.9, and 77.5 for males. These data are inconsistent with the EDTIAR label claim that the repellent provides 95% or greater protection against mosquitoes for 12 hr or more under normal use conditions. The results of a multivariate regression analysis indicated that 1) protection decreased linearly as time after application of repellent increased (P < 0.001), 2) individuals who applied higher doses of repellent were better protected against mosquito bites (P < 0.001), 3) females experienced significantly less protection over time than did males (P = 0.005), and 4) the estradiol concentration in the blood had no effect on efficacy of the repellent (P = 0.110). (+info)
Short report: prevention of Schistosoma mansoni infections in mice by the insect repellents AI3-37220 and N,N-diethyl-3-methylbenzamide.
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N,N-diethyl-3-methylbenzamide (DEET) has recently been reported to kill cercariae of Schistosoma mansoni in vitro. In addition, it blocked cercarial entry into mouse tail skin. We confirmed these results and compared the efficacy of DEET to a second insect repellent, 1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), in preventing S. mansoni infections in mice. Both AI3-37220 and DEET conferred 100% protection against S. mansoni infection via percutaneous exposure to cercariae. (+info)
Anticonvulsant-resistant seizures following pyridostigmine bromide (PB) and N,N-diethyl-m-toluamide (DEET).
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An acute toxic interaction has been described, in which sublethal doses of pyridostigmine bromide (PB) and the insect repellent N,N-diethyl-m-toluamide (DEET), when administered concomitantly, resulted in seizures and lethality. To investigate the possible relationships between seizures and lethality and the role of the cholinergic system in this interaction, PB (5 mg/kg), DEET (200 mg/kg) or PB (3 mg/kg) + DEET (200 mg/kg) were administered i.p. to male ICR mice, alone or following i.p. pretreatment, with one of several anticonvulsant agents: diazepam, 10 mg/kg; fosphenytoin, 40 mg/kg; phenobarbital, 45 mg/kg; or dextrophan, 25 mg/kg), or the anticholinergic agents, atropine (5 mg/kg), atropine methyl nitrate (2.7 mg/kg), or mecamylamine (2.5 mg/kg). The anticonvulsants selected for this study act through different mechanisms to reduce seizures. None of the anticonvulsants was able to reduce the incidence of seizures following treatment with PB, DEET or PB + DEET. Only diazepam delayed the onset of seizures. Fosphenytoin or diazepam significantly prolonged the time to lethality following PB, but only fosphenytoin reduced the incidence of PB-induced lethality. Diazepam or phenobarbital significantly prolonged the time to lethality following PB + DEET. Both atropine and atropine methyl nitrate protected against PB and PB + DEET-induced lethality and PB-induced seizures. Neither agent blocked seizures resulting from DEET or PB + DEET. Mecamylamine reduced seizures and lethality in PB-treated mice, but not in mice treated with DEET or PB + DEET. The results indicate that seizure activity is not a causative factor in the toxic interaction between PB and DEET. Furthermore, PB, DEET and PB + DEET induce seizures that are resistant to standard anticonvulsants, and each appears to operate through different mechanisms to produce seizures. Peripheral muscarinic receptors may play a specific role in lethality caused by PB + DEET. (+info)
Nitric oxide selectively decreases interferon-gamma expression by activated human T lymphocytes via a cGMP-independent mechanism.
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The role of exogenous nitric oxide (NO) on the expression of interleukin (IL)-2, IL-4, IL-5 and interferon-gamma (IFN-gamma) by freshly isolated human T lymphocytes was investigated. The presence of NO, generated from any of the NO-donor compounds, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), DPTA-nonoate (DPTA) or DETA-nonoate (DETA), added 15 min prior to T-cell stimulation (for 24 hr) with anti-CD3/anti-CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition of IL-4, IL-5 and IFN-gamma secretion. In contrast, IL-2 secretion was not inhibited. Using the guanylate cyclase inhibitor, LY83583, it was shown that the inhibition of IL-4 and IL-5 was cGMP dependent, whereas additional mechanisms mediated the inhibition of IFN-gamma. Exposure of T cells to the NO-donor compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition of IFN-gamma secretion by DPTA and DETA (P < 0.01), despite the fact that NO generation could no longer be detected. Under these conditions, IL-4 secretion was not inhibited and IL-5 secretion was inhibited to a lesser extent (P < 0.01 for SNAP and DPTA, P > 0.05 for DETA). IL-2 secretion was inhibited after 24 hr of preincubation with the NO-donor compounds, whereas it was not directly affected by NO. The increased inhibitory effects on IFN-gamma and IL-2 secretion could not be accounted for by the antiproliferative effects of the NO-donor compounds, which were diminished after 24 hr of preincubation relative to 15 min of preincubation. For IFN-gamma, the inhibition was at least partially effected at the transcriptional level as shown by decreased mRNA accumulation. These data show that NO can modulate the balance between the expression, by human T-lymphocytes, of T helper 1- and T helper 2-type cytokines, through selective and persistent inhibition of the expression of IFN-gamma via a cGMP-independent mechanism. (+info)
Development and evaluation of LIPODEET, a new long-acting formulation of N, N-diethyl-m-toluamide (DEET) for the prevention of schistosomiasis.
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N, N-diethyl-m-toluamide (DEET) is a common and fairly safe active ingredient in many insect repellents. Our recent studies showed that when applied to the skin, DEET has a potent anti-parasitic effect against Schistosoma mansoni. However, the beneficial effects of DEET lasted only for a few minutes, presumably due to its rapid absorption through the skin. In this study, we evaluated different carrier formulations that prolong the activity of DEET in the skin. Among the various formulations analyzed, DEET incorporated into liposomes (LIPODEET) appeared to prolong the activity of DEET for more than 48 hr after a single application. Furthermore, LIPODEET was found to be minimally absorbed through the skin and loss due to washing off was limited. These findings thus suggest LIPODEET is a safe and long-acting formulation of DEET that is quite effective against schistosomiasis. (+info)