Polyethylene glycol as marker for nitrofurazone allergy: 20 years of experience from Turkey.

BACKGROUND: Polyethylene glycols (PEGs) and propylene glycol (PG) are used as vehicles in various medicinal and cosmetic products. They are potential contact sensitizers, including low molecular weight PEGs in nitrofurazone preparations that are still widely used in Turkey. OBJECTIVES: To investigate the prevalence of allergic contact dermatitis caused by PEG and PG in a relatively large group of patients in Turkey. METHODS: In this retrospective, cross-sectional, single-centre study, 836 patients patch tested with PEG and PG between 1996 and 2015 were reviewed. RESULTS: Thirty-five patients (4.2%) showed positive patch test reactions to PEG, and 7 (0.8%) showed positive patch test reactions to PG, partly as late positive reactions with PEG. PEG sensitivity was almost exclusively related to nitrofurazone allergy. Patch test reactions to PG were currently relevant mainly with regard to the use of minoxidil, and antiherpetic or corticosteroid creams. Ten patients (25%) had concomitant contact allergies to various topical drugs containing mainly PEGs. CONCLUSIONS: PEG sensitivity seems to be a marker for contact allergy to topical nitrofurazone in Turkey. Nitrofurazone allergy appears to favour concomitant sensitization to PEG. We would suggest the inclusion of PEG in an extended baseline patch test series in Turkey. Late patch test readings are important to diagnose delayed positive reactions to PEG.

Foot contact dermatitis: nitrofurazone as the main cause in a retrospective, cross-sectional study over a 16-year period from Turkey.

BACKGROUND: The major causative agents in allergic contact dermatitis of the foot may differ from country to country. Sufficient data on foot eczema in patients from Turkey are lacking. OBJECTIVE: To identify the clinically relevant contact allergens in foot eczema and determine the role of patch test series and patients' own materials in the detection of the responsible allergens. METHODS: Among 1753 patients patch tested between 1996 and 2012 in our clinic, 53 with suspected allergic foot eczema were enrolled in this retrospective, cross-sectional study. Forty nine patients were patch tested with the extended European baseline series, 49 with supplemental series including rubber, leather, topical drugs, textile, cosmetic series containing preservatives and emulgators and varnish/plastic/glue series, and 37 with their own substances. RESULTS: Thirty of the 53 patch tested patients showing sensitization to at least one clinically relevant allergen were diagnosed with allergic foot eczema. The main eliciting agent was nitrofurazone (n = 8), followed by leather shoe allergens, ie, potassium dichromate (n = 6), p-tert-butylphenol formaldehyde resin and formaldehyde, in the second range. Rubber shoe allergens were less frequently observed (n = 3). In more than 1/3 of the patients, the causative agent could only be identified by testing the patient's own substances and/or supplemental series. CONCLUSION: Nitrofurazone was the leading causative agent followed by leather shoe allergens. Pediatric patients were frequently sensitized with shoe allergens. Patch testing with patient's own substances had a critical value in the detection of the causative agent in a significant number of patients.

Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole.

BACKGROUND: Treatment of Chagas disease, caused by Trypanosoma cruzi, relies on nifurtimox and benznidazole (BZL), which present side effects in adult patients, and natural resistance in some parasite strains. Hydroxymethylnitrofurazone (NFOH) is a new drug candidate with demonstrated trypanocidal activity; however, its safety is not known. METHODS: HepG2 cells dose response to NFOH and BZL (5-100 µM) was assessed by measurement of ROS, DNA damage and survival. Swiss mice were treated with NFOH or BZL for short-term (ST, 21 d) or long-term (LT, 60 d) periods. Sera levels of cellular injury markers, liver inflammatory and oxidative stress, and fibrotic remodeling were monitored. RESULTS: HepG2 cells exhibited mild stress, evidenced by increased ROS and DNA damage, in response to NFOH, while BZL at 100 µM concentration induced >33% cell death in 24 h. In mice, NFOH ST treatment resulted in mild-to-no increase in the liver injury biomarkers (GOT, GPT), and liver levels of inflammatory (myeloperoxidase, TNF-α), oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. These stress responses in NFOH LT treated mice were normalized to control levels. BZL-treated mice exhibited a >5-fold increase in GOT, GPT and TNF-α (LT) and a 20-40% increase in liver levels of MPO activity (ST and LT) in comparison with NFOH-treated mice. The liver inflammatory infiltrate was noted in the order of BZL>vehicle≥NFOH and BZL>NFOH≥vehicle, respectively, after ST and LT treatments. Liver fibrotic remodeling, identified after ST treatment, was in the order of BZL>vehicle>NFOH; lipid deposits, indicative of mitochondrial dysfunction and in the order of NFOH>vehicle>BZL were evidenced after LT treatment. CONCLUSIONS: NFOH induces mild ST hepatotoxicity that is normalized during LT treatment in mice. Our results suggest that additional studies to determine the efficacy and toxicity of NFOH are warranted.

[Damage to synaptonemal complex structure and peculiarities of selection of mouse spermatocytes I at response to drug administration].

Using immunocytochemistry methods, the structure of synaptonemal complexes (SC) of chromosomes in spread nuclei of primary spermatocytes of mice at 1, 10, and 36 days after the 10-day intraperitoneal administration of antibacterial preparations of three pharmacological groups: furacilin, an antiseptic derivative of nitrofuran; cifran, an antibiotic from the group of fluoroquinolones; and sextaphage, a polyvalent piobacteriophage was investigated. The maximal number of disturbances in the structure and behavior of synaptonemal complex was revealed on the first day after the end of preparation administration. On days 10 and 36, the total number of disturbances in SC structure decreased gradually. On the first day after the end of the administration of cifran and sextaphage in 41.8 and 25% of nuclei, respectively, the fragmentation of synaptonemal complexes was revealed and, in males to whom furacilin had been administered, the fragmentation of synaptonemal complexes was identified in 100% of nuclei. Multiple chromosome fragmentation is a meiotic disaster and results in the degeneration of cells without enabling the mechanism ofpachytene arrest. The features of pachytene arrest were revealed in the nuclei of primary spermatocytes with the disturbances of chromosomes pairing. After the administration of sextaphage, circle structures released from the lateral elements of SC and are dyed with antibodies to SCP3 protein.

Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial).

BACKGROUND: Catheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital and incurs significant costs for health-care providers such as the UK NHS. Many preventative strategies and measures have been introduced to minimise CAUTI risk, including the use of antimicrobial catheters. However, there is considerable uncertainty regarding their usefulness in terms of reducing symptomatic CAUTI, and whether or not they are cost-effective. OBJECTIVES: Do antimicrobial catheters reduce the rate of symptomatic urinary tract infection (UTI) during short-term hospital use and is their use cost-effective for the UK NHS? DESIGN: A pragmatic multicentre UK randomised controlled trial comparing three catheters as they would be used in the UK NHS: antimicrobial-impregnated (nitrofurazone) and antiseptic-coated (silver alloy) catheters with the standard polytetrafluoroethylene (PTFE)-coated catheters. Economic evaluation used a decision model populated with data from the trial. Sensitivity analysis was used to explore uncertainty. SETTING: Relevant clinical departments in 24 NHS hospitals throughout the UK. PARTICIPANTS: Adults requiring temporary urethral catheterisation for a period of between 1 and 14 days as part of their care, predominantly as a result of elective surgery. INTERVENTIONS: Eligible participants were randomised 1 : 1 : 1 to one of three types of urethral catheter in order to make the following pragmatic comparisons: nitrofurazone-impregnated silicone catheter compared with standard PTFE-coated latex catheter; and silver alloy-coated hydrogel latex catheter compared with standard PTFE-coated latex catheter. MAIN OUTCOME MEASURES: The primary outcome for clinical effectiveness was the incidence of UTI at any time up to 6 weeks post randomisation. This was defined as any symptom reported during catheterisation, up to 3 days or 1 or 2 weeks post catheter removal or 6 weeks post randomisation combined with a prescription of antibiotics, at any of these times, for presumed symptomatic UTI. The primary economic outcome was incremental cost per quality-adjusted life-year (QALY). Health-care costs were estimated from NHS sources with QALYs calculated from participant completion of the European Quality of Life-5 Dimensions (EQ-5D). RESULTS: Outcome analyses encompassed 6394 (90%) of 7102 participants randomised. The rate of symptomatic UTI within 6 weeks of randomisation was 10.6% in the nitrofurazone group (n = 2153; -2.1% absolute risk difference), 12.5% in the silver alloy group (n = 2097; -0.1% absolute risk difference) and 12.6% in the PTFE group (n = 2144). The effect size {odds ratio (OR) [97.5% confidence interval (CI)]} was 0.82 (97.5% CI 0.66 to 1.01) for nitrofurazone (p = 0.037) and 0.99 (97.5% CI 0.81 to 1.22) for silver alloy (p = 0.92) catheters. The nitrofurazone catheters were more likely to cause discomfort during use and on removal. The primary economic analysis suggested that nitrofurazone-impregnated catheters would be, on average, the least costly (> £7 less than PTFE) and most effective option at current NHS prices. There was a 73% chance that nitrofurazone would be cost saving and an 84% chance that the incremental cost per QALY would be < £30,000. At the trial price (£6.46), silver alloy catheters were very unlikely to be cost-effective. These results were unchanged in sensitivity analyses, although when the length of stay cost was excluded the incremental cost per QALY for nitrofurazone against PTFE was £28,602. CONCLUSIONS: The trial estimate of clinical effectiveness for nitrofurazone-impregnated catheters was less than the pre-specified minimum absolute risk difference that we considered important (-3.3%), and the surrounding CI included zero, indicating that any reduction in catheter-associated UTI was uncertain. Economic analysis, although associated with uncertainty, suggested that nitrofurazone-impregnated catheters may be cost-effective for the NHS. The trial ruled out the possibility that silver alloy-coated catheters might reach the pre-set degree of clinical effectiveness and that their use was unlikely to be cost-effective. These findings should be considered by patients, clinicians and health-care policy-makers to determine whether or not a change in practice is worthwhile. Future research should be aimed at determining the minimum clinically important difference in terms of CAUTI prevention in comparative trials, and to identify reliable methods which can detect the impact of the intervention on quality of life and other drivers of cost, when the intervention is a subsidiary part of overall treatment plans.

Voltammetric investigation of DNA damage induced by nitrofurazone and short-lived nitro-radicals with the use of an electrochemical DNA biosensor.

Electrochemical behavior of nitrofurazone (NFZ) was investigated with the use of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The pH-dependence of NFZ was studied at a glassy carbon electrode (GCE) in ethanol/Britton-Robinson buffer (30:70), and short-lived nitro-radicals were generated by the reduction of NFZ at high pHs (>7.0). In the presence of DNA, the DPV peak current of NFZ decreased and the peak potential shifted negatively, which indicated that there was an electrostatic interaction between NFZ and DNA. An electrochemical dsDNA/GCE biosensor was prepared to study the DNA damage produced in the presence NFZ; this process was followed with the use of the Co(phen)(3)(2+) electroactive probe. Also, the oxidation peaks of guanosine (750 mV) and adenosine (980 mV) indicated that DNA damage was related directly to the nitro-radicals. Experiments demonstrated that DNA damage occurred via two different steps while NFZ was metabolized and nitro-radicals were produced. Novel work with AFM on the NFZ/DNA interaction supported the suggestion that in vivo, the nitro-radicals were more cytotoxic than the NFZ molecules. A linear DPV calibration plot was obtained for NFZ analysis at a modified dsDNA/GCE (concentration range: 2.50 × 10(-6)-3.75 × 10(-5) mol L(-1); limit of detection: 8.0 × 10(-7) mol L(-1)), and NFZ was determined successfully in pharmaceutical samples.

Hipersensibilidad a los nitrofuranos / Nitrofurane hypersensitivity

Antecedentes y objetivos: La nitrofurantoína y la nitrofurazona son antibacterianos de amplio espectro que se emplean como antinfecciosos urinario y dermatológico, respectivamente. Material y métodos: Presentamos dos casos de hipersensibilidad a los nitrofuranos, uno con una anafilaxia tras la ingestión de nitrofurantoína y otro con una reacción local de dermatitis de contacto tras la aplicación tópica de nitrofurazona. Resultados y conclusiones: El estudio alergológico con pruebas cutáneas y determinación de IgE frente a nitrofurantoína en el caso de la anafilaxia (mecanismo de hipersensibilidad del tipo I) y con pruebas epicutáneas a nitrofurazona en el caso de la dermatitis de contacto (mecanismo de hipersensibilidad del tipo IV) fue positivo; ambos pacientes toleraron otros nitrofuranos no implicados en la reacción. Encontramos pocos casos de alergia a estos fármacos en la literatura revisada. Aunque en el caso de nuestros pacientes no existió reactividad cruzada con otros fármacos que contienen el anillo furano, para poder confirmar esta observación se necesitan más estudios

Introduction: Nitrofurantoin and nitrofurazone are antibacterial agents used in urinary tract and cutaneous infections respectively. Material and methods: Two cases of hypersensitivity are presented, one with anaphylaxis after taking nitrofurantoin and another with a localized reaction of contact dermatitis after using nitrofurazone. Results and conclusions: In both cases the allergic examination including skin tests and IgE determinations with nitrofurantoin in the case of anaphilaxis and with epicutaneous tests for nitrofurazone in the case of contact dermatitis was positive; both tolerated other nitrofurans not involved in the reaction. We found few cases of allergy to these drugs in the revised literature. Although in our cases there was no cross reactivity among nitrofurans, more estudies are necessary in order to confirm that this is a general rule

Effect of dental adhesives on the exudative phase of the inflammatory process in subcutaneous tissue of rats.

The vascular changes in the subcutaneous connective tissue of rats induced by dentin bonding systems (one step) was studied and compared to those induced by saline solution (negative control) and Furacin (positive control), during the exudative phase of the inflammatory process. Twenty mg/kg of Evan's blue were injected intravenously in the vein of the rats' penises; 0.1 ml of each substance tested was inoculated in the subcutaneous tissue. After a 3 hour period the animals were sacrificed and their skins were excised and punched out with a standard steel 2.5 cm in diameter. The specimens were immediately immersed in 8 ml of formamide and taken to a double boiler for 72 hours at 37 C, to remove the dye. The liquid containing the overflowed dye was filtered, analyzed in the spectrophotometer (620 nm) and classified according to the criteria established by Nagem-Filho, Pereira (1976). After statistical analysis, the irritative potential of the substances was ranked as follows: Furacin (severe) > Single Bond and Bond 1 (moderate - no significant differences between the dentin bonding systems tested) > saline solution (not significant as regards the irritation degree).

Effect of dental adhesives on the exudative phase of the inflammatory process in subcutaneous tissue of rats

The vascular changes in the subcutaneous connective tissue of rats induced by dentin bonding systems (one step) was studied and compared to those induced by saline solution (negative control) and Furacin (positive control), during the exudative phase of the inflammatory process. Twenty mg/kg of Evan's blue were injected intravenously in the vein of the rats' penises; 0.1 ml of each substance tested was inoculated in the subcutaneous tissue. After a 3 hour period the animals were sacrificed and their skins were excised and punched out with a standard steel 2.5 cm in diameter. The specimens were immediately immersed in 8 ml of formamide and taken to a double boiler for 72 hours at 37ºC, to remove the dye. The liquid containing the overflowed dye was filtered, analyzed in the spectrophotometer (620 nm) and classified according to the criteria established by Nagem-Filho, Pereira (1976). After statistical analysis, the irritative potential of the substances was ranked as follows: Furacin (severe) > Single Bond and Bond 1 (moderate - no significant differences between the dentin bonding systems tested) > saline solution (not significant as regards the irritation degree)

Allergic contact dermatitis to polyethylene glycol and nitrofurazone.

We report a case of worsening dermatitis after the application of an antibiotic ointment (Furacin) containing furazone and polyethylene glycol. Patch tests to nickel sulfate, potassium dischromate, chloride cobalt, Furacin, nitrofurazone 1% petrolatum, polyethylene glycol mix 4% petrolatum, polyethylene glycol (PEG) 300 4% petrolatum, and PEG 400 as is (ai) were positive. The use of topical agents containing nitrofurazone or polyethylene glycol on damaged skin may predispose to contact allergy. We discuss the sensitizing properties of nitrofurazone and polyethylene glycol.