Proteome Changes Induced by Iprodione Exposure in the Pesticide-Tolerant Pseudomonas sp. C9 Strain Isolated from a Biopurification System.

Iprodione is a pesticide that belongs to the dicarboximide fungicide family. This pesticide was designed to combat various agronomical pests; however, its use has been restricted due to its environmental toxicity and risks to human health. In this study, we explored the proteomic changes in the Pseudomonas sp. C9 strain when exposed to iprodione, to gain insights into the affected metabolic pathways and enzymes involved in iprodione tolerance and biodegradation processes. As a result, we identified 1472 differentially expressed proteins in response to iprodione exposure, with 978 proteins showing significant variations. We observed that the C9 strain upregulated the expression of efflux pumps, enhancing its tolerance to iprodione and other harmful compounds. Peptidoglycan-binding proteins LysM, glutamine amidotransferase, and protein Ddl were similarly upregulated, indicating their potential role in altering and preserving bacterial cell wall structure, thereby enhancing tolerance. We also observed the presence of hydrolases and amidohydrolases, essential enzymes for iprodione biodegradation. Furthermore, the exclusive identification of ABC transporters and multidrug efflux complexes among proteins present only during iprodione exposure suggests potential counteraction against the inhibitory effects of iprodione on downregulated proteins. These findings provide new insights into iprodione tolerance and biodegradation by the Pseudomonas sp. C9 strain.

Genotoxic effects induced by iprodione and tebuconazole in meristematic cells of Allium cepa: responses dependent on concentration and exposure time.

The present work explores the genotoxicity of the fungicides iprodione (IP) and tebuconazole (TB) using the Allium cepa assay as an in vivo biological model. Both short-term and long-term exposures were studied, revealing concentration- and time-dependent cytological and genotoxic effects. IP exhibited genotoxicity over a wider concentration range (5-50 µg/ml) and required 30 h of exposure, while TB showed genotoxicity at higher concentrations (10 and 30 µg/ml) within a 4-h exposure period. The study highlights the importance of assessing potential risks associated with fungicide exposure, including handling, disposal practices, and concerns regarding food residue. Moreover, the research underscores the genotoxic effects of IP and TB on plant cells and provides valuable insights into their concentration and time-response patterns.

Embryotoxic effects of Rovral® for early chicken (Gallus gallus) development.

Rovral® is a fungicide used to control pests that affect various crops and little is known regarding its effects on embryonic development of amniotes. Thus, this study aimed to determine the influence of Rovral® during chicken organogenesis using acute in ovo contamination. Fertilized eggs were inoculated with different concentrations of Rovral® (100, 300, 500 or 750 µl/ml), injected into the egg's air chamber. After 7 days, embryos were examined for possible malformations, staging, weight and mortality. Subsequently, head, trunk, limbs and eyes were measured for morphometry and asymmetry. For blood analysis, eggs were treated with 300 µl/ml Rovral® and glucose, presence of micronuclei and erythrocyte nuclei abnormalities determined. Treatments with Rovral® affected the mortality rate in a concentration-dependent manner. LC50 value was found to be 596 µl/ml which represents 397-fold higher than the recommended concentration for use. Rovral® produced several malformations including hemorrhagic, ocular and cephalic abnormalities. No significant changes were observed in body weight, staging, body measurements, symmetry and glucose levels of live embryos, which indicates this fungicide presents low toxicity under the analyzed conditions. Changes in erythrocyte nuclei were noted; however significant difference was observed only for presence of binucleated erythrocytes. It is important to point out that possibly more significant changes may have occurred at lower concentrations through chronic contamination. Therefore, caution is needed in the use of this fungicide, since it presents teratogenic and mutagenic potential.

Dose-independent genotoxic response in A549 cell line exposed to fungicide Iprodione.

The fungicide Iprodione is widely applied in vegetables and raises concern for human health. The A549 human lung carcinoma cell line is a suitable model for assessing the toxicological effects of drugs. The goal of this work was to evaluate the genotoxicity and oxidative stress in the A549 cell line exposed to sublethal concentrations from 3 to 100 µg/mL Iprodione considering LC50 = 243.4 µg/mL Iprodione, as determined by the MTT assay. Generalized Linear Mixed Models (GLMM) were performed to determine the association between the responses NDI, MNim and MNib and the explanatory variables. Iprodione and solvent were relativized to the control whereas the concentration was included as numeric variable. ANOVA was used for the comparison of treatments. The coefficients of linear association between the explanatory variables and NDI, and the coefficients of logistic association between explanatory variables and MNim were not significant. However, these coefficients showed significant association with MNib only for Iprodione treatment but not for Iprodione concentration, indicating lack of dose-response relationship. Genotoxicity risk assessment indicated that the increase in Iprodione concentrations increased slightly the probability of belonging to the genotoxic category. ANOVA showed significant differences in MNib, and non-significant differences in NDI and MNim among treatments. The oxidative stress analysis performed at 3, 12, and 25 µg/mL Iprodione showed a significant and linear increase in SOD, and a significant and linear decrease in GSH and GST. The Dunnett test was significant for GSH at 12 and SOD at 25 µg/mL.

Pesticide-tolerant bacteria isolated from a biopurification system to remove commonly used pesticides to protect water resources.

In this study, we selected and characterized different pesticide-tolerant bacteria isolated from a biomixture of a biopurification system that had received continuous applications of a pesticides mixture. The amplicon analysis of biomixture reported that the phyla Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria were predominant. Six strains grew in the presence of chlorpyrifos and iprodione. Biochemical characterization showed that all isolates were positive for esterase, acid phosphatase, among others, and they were identified as Pseudomonas, Rhodococcus and Achromobacter based on molecular and proteomic analysis. Bacterial growth decreased as both pesticide concentrations increased from 10 to 100 mg L-1 in liquid culture. The Achromobacter sp. strain C1 showed the best chlorpyrifos removal rate of 0.072-0.147 d-1 a half-life of 4.7-9.7 d and a maximum metabolite concentration of 2.10 mg L-1 at 120 h. On the other hand, Pseudomonas sp. strain C9 showed the highest iprodione removal rate of 0.100-0.193 d-1 a half-life of 4-7 d and maximum metabolite concentration of 0.95 mg L-1 at 48 h. The Achromobacter and Pseudomonas strains showed a good potential as chlorpyrifos and iprodione-degrading bacteria.

Cytogenotoxic activity of the pesticides imidacloprid and iprodione on Allium cepa root meristem.

Effects of imidacloprid and iprodione, isolated and in mixture, were assessed by using seed germination and root growth test, flow cytometry, and chromosomal aberrations test on Allium cepa root meristem. The highest concentrations of imidacloprid, including field concentration, increased the frequency of sub-G1 particles, decreased the frequency of nuclei in G2/M, increased the coefficient of variation of G1 (CVG1) and the frequency of aberrant cells, and inhibited the mitotic index culminating in the reduction in root length. All doses of iprodione also presented cytogenotoxic action. The highest concentration of the fungicide affected the growth of A. cepa roots. In response to exposure to pesticide mixtures, the cell cycle of A. cepa was blocked in the G1 phase. The mixtures with low doses of the pesticides significantly decreased the mitotic index, and as a consequence, the genotoxicity was reduced. In the mixtures with the highest doses of the agrochemicals, the blockage of the cell cycle was insufficient for damage repair, resulting in a significant increase of chromosomal aberrations. The results suggest caution in the use of pesticides doses that induce cytological abnormalities in non-target organisms.

Low-cost sugarcane bagasse and peanut shell magnetic-composites applied in the removal of carbofuran and iprodione pesticides.

In the present study, two agro-industrial wastes, sugarcane bagasse, and peanut shell were employed as support of magnetite nanoparticles for the synthesis of magnetic bio-composites: magnetic sugarcane bagasse (MBO) and magnetic peanut shell (MPSo). The presence of magnetite was verified by Raman spectroscopy. Magnetic nanoparticles shape and size distribution were studied by TEM, while composites morphologies were observed by SEM. Structural characteristics of the pesticides and their possible chemical adsorption on composites were analyzed by FTIR. The removal was carried out by a batch adsorption process, and UV-VIS technique was used for pesticide concentration estimation. Elovich model described better all systems pointing out to a chemical adsorption process occurring. Experimental data isotherms of carbofuran and iprodione can be best explained by more than one mathematical model, but Sip was the ordinary equation in all systems. Maximum adsorption capacities of 175 and 89.3 mg/g for carbofuran, and 119 and 2.76 mg/g for iprodione, were obtained for MBo and MPSo, respectively.

The fungicide iprodione affects midgut cells of non-target honey bee Apis mellifera workers.

The honey bee Apis mellifera is an important pollinator of agricultural crops and natural forests. Honey bee populations have declined over the years, as a result of diseases, pesticides, and management problems. Fungicides are the main pesticides found in pollen grains, which are the major source of protein for bees. The objective of this study was to evaluate the cytotoxic effects of the fungicide iprodione on midgut cells of adult A. mellifera workers. Bees were fed on iprodione (LD50, determined by the manufacturer) for 12 or 24 h, and the midgut was examined using light and transmission electron microscopies. The expression level of the autophagy gene atg1 was assessed in midgut digestive cells. Cells of treated bees had signs of apoptosis: cytoplasmic vacuolization, apical cell protrusions, nuclear fragmentation, and chromatin condensation. Ultrastructural analysis revealed some cells undergoing autophagy and necrosis. Expression of atg1 was similar between treated and control bees, which can be explained by the facts that digestive cells had autolysosomes, whereas ATG-1 is found in the initial phases of autophagy. Iprodione acts by inhibiting the synthesis of glutathione, leading to the generation of reactive oxygen species, which in turn can induce different types of cell death. The results indicate that iprodione must be used with caution because it has side effects on non-target organisms, such as pollinator bees.

Toxicological effects of comercial formulations of fungicides based on procymidone and iprodione in seedlings and root tip cells of Allium cepa.

In this study the phytotoxic, cytotoxic, genotoxic and mutagenic effects of two commercial fungicide-active compounds, procymidone (PR) and iprodione (IP), were determined. The parameters evaluated were germination and root growth, mitotic index, chromosomal and nuclear aberrations, and molecular analyses were also performed in the model plant Allium cepa L. The results demonstrated that the active compounds PR and IP were phytotoxic, delaying germination and slowing the development of A. cepa seedlings. Moreover, PR and IP showed cytogenotoxicity towards A. cepa meristematic cells, inducing chromosomal changes and cell death. The mutagenic activity of the active compounds was demonstrated by the detection of DNA changes in simple sequence repeat (SSR) and inter-simple sequence repeat (ISSR) markers in the treated cells compared to the negative control. Together, these results contribute to a better understanding of the damage caused by these substances in living organisms and reveal a promising strategy for prospective studies of the toxic effects of environmental pollutants.

Leptin Elicits LTC4 Synthesis by Eosinophils Mediated by Sequential Two-Step Autocrine Activation of CCR3 and PGD2 Receptors.

Leptin is a cytokine, produced mainly by mature adipocytes, that regulates the central nervous system, mainly to suppress appetite and stimulate energy expenditure. Leptin also regulates the immune response by controlling activation of immunomodulatory cells, including eosinophils. While emerging as immune regulatory cells with roles in adipose tissue homeostasis, eosinophils have a well-established ability to synthesize pro-inflammatory molecules such as lipid mediators, a key event in several inflammatory pathologies. Here, we investigated the impact and mechanisms involved in leptin-driven activation of eicosanoid-synthesizing machinery within eosinophils. Direct in vitro activation of human or mouse eosinophils with leptin elicited synthesis of lipoxygenase as well as cyclooxygenase products. Displaying selectivity, leptin triggered synthesis of LTC4 and PGD2, but not PGE2, in parallel to dose-dependent induction of lipid body/lipid droplets biogenesis. While dependent on PI3K activation, leptin-driven eosinophil activation was also sensitive to pertussis toxin, indicating the involvement of G-protein coupled receptors on leptin effects. Leptin-induced lipid body-driven LTC4 synthesis appeared to be mediated through autocrine activation of G-coupled CCR3 receptors by eosinophil-derived CCL5, inasmuch as leptin was able to trigger rapid CCL5 secretion, and neutralizing anti-RANTES or anti-CCR3 antibodies blocked lipid body assembly and LTC4 synthesis induced by leptin. Remarkably, autocrine activation of PGD2 G-coupled receptors DP1 and DP2 also contributes to leptin-elicited lipid body-driven LTC4 synthesis by eosinophils in a PGD2-dependent fashion. Blockade of leptin-induced PGD2 autocrine/paracrine activity by a specific synthesis inhibitor or DP1 and DP2 receptor antagonists, inhibited both lipid body biogenesis and LTC4 synthesis induced by leptin stimulation within eosinophils. In addition, CCL5-driven CCR3 activation appears to precede PGD2 receptor activation within eosinophils, since neutralizing anti-CCL5 or anti-CCR3 antibodies inhibited leptin-induced PGD2 secretion, while it failed to alter PGD2-induced LTC4 synthesis. Altogether, sequential activation of CCR3 and then PGD2 receptors by autocrine ligands in response to leptin stimulation of eosinophils culminates with eosinophil activation, characterized here by assembly of lipidic cytoplasmic platforms synthesis and secretion of the pleiotropic lipid mediators, PGD2, and LTC4.

Sensitivity of Botrytis cinerea Isolates from Conventional and Organic Strawberry Fields in Brazil to Azoxystrobin, Iprodione, Pyrimethanil, and Thiophanate-Methyl.

Botrytis fruit rot, caused by Botrytis cinerea, is one of the most important strawberry diseases worldwide, and fungicide applications are often used to manage the disease in commercial production. Isolates of B. cinerea were collected from conventional and organic strawberry fields in four Brazilian States from 2013 to 2015 and their sensitivity to the main single-site mode-of action fungicides used in Brazil was tested. Resistance to azoxystrobin, iprodione, pyrimethanil, and thiophanate-methyl was found and values for effective concentration that inhibited mycelial growth by 50% were higher than 71.9, 1.2, 5.0, and 688 µg/ml, respectively, regardless the production system. Resistance to these fungicides was observed in 87.5, 76.6, 23.4, and 92.2% of isolates from conventional fields and 31.4, 22.9, 14.3, and 51.4% of isolates from organic fields, respectively. Moreover, frequencies of isolates with multiple fungicide resistance to the four active ingredients were 20.6 and 2.8% whereas 6.3 and 27.8% were sensitive to the four fungicides for conventional and organic areas, respectively. Molecular analyses of the cytochrome b, ß-tubulin, and bos1 genes revealed the presence of G143A; E198A; and I365 N/S, Q369P, or N373S mutations, respectively, in resistant isolates of B. cinerea. Field rates of fungicides sprayed preventively to inoculated strawberry fruit failed to control disease caused by the respective resistant isolates.

Novel insights in biopurification system for dissipation of a pesticide mixture in repeated applications.

A biopurification system based on the adsorption and degradation capacity of a biomixture to degrade a mixture of pesticides (atrazine, chlorpyrifos, iprodione; 50 mg kg-1 each) in repeated applications (0, 30, and 60 days) was evaluated. Tanks of 1 m3 packed with a biomixture (ρ 0.29 g mL-1) with and without vegetal cover were used. The biomixture contained soil, peat, and wheat straw in a proportion 1:1:2 by volume, respectively. Pesticide concentrations, biological activities (urease, phenoloxidase, and dehydrogenase), and microbial community changes (DGGE and qPCR) were evaluated periodically. Pesticide dissipation was higher in tanks with vegetal cover (> 95%) and no variation was observed after the three applications; contrarily, pesticide dissipation decreased in the tank without vegetal cover after each application. The presence of vegetal cover decreased the half-life of pesticides by at least twice. Biological activities were in general not affected by the application and reapplication of pesticides in the same treatment; however, they exhibited some differences between tanks containing and lacking the vegetal cover. High similarity between microbial groups (actinobacteria, bacteria, and fungi) was observed, suggesting no influence ascribable to the successive pesticide applications. The number of copies of bacteria and actinobacteria remained almost constant during the assay. However, the number of copies of fungi was significantly higher in the uncontaminated tank without vegetal cover.

Atrazine, chlorpyrifos, and iprodione effect on the biodiversity of bacteria, actinomycetes, and fungi in a pilot biopurification system with a green cover.

The use of biopurification systems can mitigate the effects of pesticide contamination on farms. The primary aim of this study was to evaluate the effect of pesticide dissipation on microbial communities in a pilot biopurification system. The pesticide dissipation of atrazine, chlorpyrifos and iprodione (35 mg kg-1 active ingredient [a.i.]) and biological activity were determined for 40 days. The microbial communities (bacteria, actinomycetes and fungi) were analyzed using denaturing gradient gel electrophoresis (DGGE). In general, pesticide dissipation was the highest by day 5 and reached 95%. The pesticides did not affect biological activity during the experiment. The structure of the actinomycete and bacterial communities in the rhizosphere was more stable during the evaluation than that in the communities in the control without pesticides. The rhizosphere fungal communities, detected using DGGE, showed small and transitory shifts with time. To conclude, rhizosphere microbial communities were not affected during pesticide dissipation in a pilot biopurification system.

Results of a curtailed randomized controlled trial, evaluating the efficacy and safety of azimilide in patients with implantable cardioverter-defibrillators: The SHIELD-2 trial.

BACKGROUND: Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients. METHODS: A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%. The primary outcome metric was the adjudicated time-to-first unplanned cardiovascular (CV) hospitalization, or CV emergency department (ED) visit, or CV death. The trial was prematurely discontinued due to withdrawal of study sponsorship. RESULTS: Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the azimilide group. Neutropenia was not observed (absolute neutrophil count <1000 µ/L), and there was one possible torsade de pointes case that led to a successful ICD discharge. CONCLUSION: The SHIELD-2 trial was statistically underpowered due to early trial termination and did not meet its primary objective. Despite this limitation, azimilide showed promise as a safe and effective drug in reducing all-cause shocks, unplanned hospitalizations, and ED visits in ICD patients.

Tradescantia as a biomonitor for pesticide genotoxicity evaluation of iprodione, carbaryl, dimethoate and 4,4'-DDE.

There is a current tendency to develop and apply environmentally friendly techniques that meet the requirements of green analytical chemistry as an alternative to conventional analytical methods. For toxicity evaluation, these alternatives may be found in bioassays such as Tradescantia. This technique, developed in the 1980s, is highly sensitive to evaluate environmental mutagens, simple and cheap. In this paper, the sensibility of both the Tradescantia micronucleus bioassay (Trad-MCN) and the Tradescantia stamen hair bioassay (Trad-SH) were studied for carbaryl, dimethoate and iprodione, common agricultural and domestic pesticides that are currently used in Chile, which have never been tested with such bioassays. Biomonitor exposures were performed by capillary absorption for each individual pesticide over a wide range of concentrations, from maximum residue limits (trace levels) up to the application dose in agricultural fields. In addition, the organochloride 4,4'-DDE was included but only in the concentration range from 0.01mgL-1 to 1mgL-1, mimicking residue concentrations since it is not a commercial product but, rather, the main breakdown product of the persistent organochloride pesticide 4,4-DDT, whose use was discontinued in Chile in the 1980s. The Trad-MCN bioassay revealed a significant increase in micronucleus frequency at the early tetrads of meiotic pollen mother cells of the biomonitor Tradescantia pallida var. purpurea, induced by 4,4'-DDE (for 1mgL-1), dimethoate (for 40mgL-1, 200mgL-1, 400mg/L-1) and carbaryl (for 889mgL-1). Iprodione did not generate any significant change at the tested concentration. Meanwhile, the Trad-SH bioassay was carried out by analysis of the phenotype variations of the stamen hair cells of the Tradescantia clone KU-20 for the same pesticides and doses. This bioassay was not sufficiently sensitive for toxicity evaluation of most of the pesticides tested, with exception of dimethoate in low doses (2 and 5mg/L-1).

Bioaugmentation and rhizosphere-assisted biodegradation as strategies for optimization of the dissipation capacity of biobeds.

Biobeds are on-farm biodepuration systems whose efficiency rely on their high pesticide biodegradation capacity. We evaluated two optimization strategies, bioaugmentation and/or rhizosphere-assisted biodegradation, to maximize the dissipation capacity of biobeds. Iprodione was used as a model pesticide. Its dissipation and metabolism was determined in a biobed packing material inoculated with an iprodione-degrading Arthrobacter strain C1 (bioaugmentation, treatments B+C1) and/or seeded with ryegrass (rhizosphere-assisted biodegradation, treatments B+P). The impact of those strategies on the activity and composition of the microbial community was determined. Bioaugmentation accelerated the dissipation of iprodione which was further enhanced in the bioaugmented, rhizosphere-assisted treatment (treatment B+P+C1, Half-life (DT50) = 3.4 d), compared to the non-bioaugmented, non rhizosphere-assisted control (DT50 = 9.5 d, treatment B). Bioaugmentation resulted in the earlier formation of intermediate formation of metabolites I (3,5-dichlorophenyl-carboxamide), II (3,5-dichlorophenylurea acetate) and 3,5-dichloroaniline (3,5-DCA). The latter was further dissipated by the indigenous microbial community. Acid phosphatase (AP) and ß-glucosidase (GLU) were temporarily stimulated in rhizosphere-assisted treatments, whereas a stimulation of the fluorescein diacetate (FDA) hydrolytic activity in the bioaugmented treatments coincided with the hydrolysis of iprodione. q-PCR showed that changes in the abundance of alpha-proteobacteria and firmicutes was driven by the presence of rhizosphere while bioaugmentation had no significant effect.

Novel insights into the metabolic pathway of iprodione by soil bacteria.

Microbial degradation constitutes the key soil dissipation process for iprodione. We recently isolated a consortium, composed of an Arthrobacter sp. strain C1 and an Achromobacter sp. strain C2, that was able to convert iprodione to 3,5-dichloroaniline (3,5-DCA). However, the formation of metabolic intermediates and the role of the strains on iprodione metabolism remain unknown. We examined the degradation of iprodione and its suspected metabolic intermediates, 3,5-dichlorophenyl-carboxamide (metabolite I) and 3,5-dichlorophenylurea-acetate (metabolite II), by strains C1 and C2 and their combination under selective (MSM) and nutrient-rich conditions (LB). Bacterial growth during degradation of the tested compounds was determined by qPCR. Strain C1 rapidly degraded iprodione (DT50 = 2.3 h) and metabolite II (DT50 = 2.9 h) in MSM suggesting utilization of isopropylamine, transiently formed by hydrolysis of iprodione, and glycine liberated during hydrolysis of metabolite II, as C and N sources. In contrast, strain C1 degraded metabolite I only in LB and growth kinetics suggested the involvement of a detoxification process. Strain C2 was able to transform iprodione and its metabolites only in LB. Strain C1 degraded vinclozolin, a structural analog of iprodione, and partially propanil, but not procymidone and phenylureas indicating a structure-dependent specificity related to the substituents of the carboxamide moiety.

Acute generalized exanthematous pustulosis related to phenytoin administration. Case report / Pustulosis exantemática aguda generalizada relacionada al uso de fenitoína. Reporte de caso

The occurrence of acute generalized exanthematous pustulosis adverse reactions to medication administration is becoming more frequent. This article reports the case of a 78-year-old woman who attended the clinic with generalized papules and pustules on the scalp, trunk and limbs, with a concordant histology study and who was diagnosed with acute generalized exanthematous pustulosis (AGEP) associated with the use of phenytoin, a medication that may cause different skin reactions and that has been previously related to this disease. The patient was treated with systemic steroids and the disease had a satisfactory outcome.

La aparición de reacciones adversas a medicamentos del tipo pustulosis exantemática generalizada aguda es cada vez más frecuente. Se presenta el caso de una paciente de 78 años quien acude a consulta presentando unas pápulas y pústulas generalizadas en cuero cabelludo, tronco y extremidades, con estudio de histología compatible y a la que se le diagnostica pustulosis exantemática aguda generalizada (PEAG) asociada al uso de fenitoína, una medicación que puede provocar distintas reacciones cutáneas y que previamente se ha asociado a esta enfermedad. La paciente es tratada con esteroides sistémicos y la enfermedad llega a una resolución satisfactoria

Antinociceptive effect of hydantoin 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione in mice.

Imidazolidine derivatives, or hydantoins, are synthetic compounds with different therapeutic applications. Many imidazolidine derivatives have psychopharmacological properties, such as phenytoin, famous for its anticonvulsant efficacy, but also effective in the treatment of neuropathic pain. The hydantoin, 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione (IM-3), synthesized from the amino acid, glycine, was selected for psychopharmacological studies in mice on the basis of its chemical and structural similarity with phenytoin. The first step of this study was to define the LD50, which determined the doses of 50, 100 and 200 mg/kg for subsequent tests. The results obtained from the behavioral screening indicated that IM-3 produces decreased ambulation and analgesia in mice. Motor coordination and anxiety behavior were not affected by treatment with IM-3, as observed in the rotarod and elevated plus-maze tests, respectively. Regarding its antinociceptive properties, IM-3 showed efficacy in the acetic acid-induced writhing test by increasing the latency of the first writhe and reducing the number of writhes, as well as reducing the paw licking time in the second phase of the formalin test. The behavior of treated animals exposed to the hot plate test, however, did not differ from that of the control group. These data suggest that IM-3 has antinociceptive effects in mice, which is probably mediated by anti-inflammatory mechanisms.

Microsomal oxidative stress induced by NADPH is inhibited by nitrofurantoin redox biotranformation.

Nitrofurantoin is used in the antibacterial therapy of the urinary tract. This therapy is associated with various adverse effects whose mechanisms remain unclear. Diverse studies show that the nitro reductive metabolism of nitrofurantoin leads to ROS generation. This reaction can be catalyzed by several reductases, including the cytochrome P450 (CYP450) reductase. Oxidative stress arising from this nitro reductive metabolism has been proposed as the mechanism underlying the adverse effects associated with nitrofurantoin. There is, however, an apparent paradox between these findings and the ability of nitrofurantoin to inhibit lipid peroxidation provoked by NADPH in rat liver microsomes. This work was aimed to show the potential contribution of different enzymatic systems to the metabolism of this drug in rat liver microsomes. Our results show that microsomal lipid peroxidation promoted by NADPH is inhibited by nitrofurantoin in a concentration-dependent manner. This suggests that the consumption of NADPH in microsomes can be competitively promoted by lipid peroxidation and nitrofurantoin metabolism. The incubation of microsomes with NADPH and nitrofurantoin generated 1-aminohidantoin. In addition, the biotransformation of a classical substrate of CYP450 oxidative system was competitively inhibited by nitrofurantoin. These results suggest that nitrofurantoin is metabolized through CYP450 system. Data are discussed in terms of the in vitro redox metabolism of nitrofurantoin.