RESUMEN
Zeolitic Imidazolate (metal organic) Frameworks (ZIFs) and Prussian Blue Analogues (PBAs) are promising materials in electrochemical sensing due to their unique properties. In this study, a composite material comprising NiFe-PBA and ZIF-67 was synthesized and made to form a uniform layer onto a glassy carbon electrode (GCE) to enhance electrochemical performance for furazolidone (FZD) detection. The synthesized NiFe-PBA/ZIF-67 composite exhibited excellent sensitivity, selectivity, and stability towards FZD detection, with a low limit of detection (LOD). The electrochemical behaviour of FZD on the NiFe-PBA/ZIF-67/GCE electrode was investigated, revealing a diffusion-controlled process. Differential pulse voltammetry (DPV) analysis demonstrated the synergetic effect of the PBA/MOF core-shell structure in enhancing FZD electro-reduction. The sensor exhibited exceptional LOD of 0.007 µM. Selectivity studies confirmed the sensor's ability to distinguish FZD from potential interferents. Extensive evaluations demonstrated the sensor's reproducibility, repeatability, and long-term stability, affirming its practical utility. Real sample analysis further validated the sensor's excellent analytical capabilities in diverse matrices.
Asunto(s)
Técnicas Electroquímicas , Ferrocianuros , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/química , Técnicas Electroquímicas/métodos , Ferrocianuros/química , Electrodos , Estructuras Metalorgánicas/química , Furazolidona/análisis , Furazolidona/química , Límite de Detección , Carbono/química , Zeolitas/química , ImidazolesRESUMEN
Tannic acid (TA), as a stabilizing agent, was successfully utilized to establish blue-emitting copper nanoclusters (TA-Cu NCs) on the basis of a facile chemical reduction preparation method. Characterization results proved successful synthesis of TA-Cu NCs with uniform size and excellent stability. TA-Cu NCs exhibited a blue emission wavelength at 431 nm when excited at 364 nm. Interestingly, the as-prepared TA-Cu NCs were selectively quenched by furazolidone based on static quenching. In addition, this analysis platform for furazolidone detection had an excellent linear range from 0.5 to 120 µM with a detection limit of 0.074 µM (S/N = 3). Furthermore, the accuracy of this sensing method was successfully confirmed by detecting furazolidone in bovine serum samples, indicating that TA-Cu NCs had bright application prospects.
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Cobre , Nanopartículas del Metal , Polifenoles , Cobre/química , Furazolidona , Espectrometría de Fluorescencia , Colorantes Fluorescentes/química , Nanopartículas del Metal/químicaRESUMEN
Based on the peroxidase activity of Cu-hemin metal-organic framework (Cu-hemin MOF) nanozyme, a colorimetric enzyme-linked immunosensor was developed for the detection of furazolidone (FZD). Cu-hemin MOF is a bimetallic nanozyme that exhibited a stronger catalytic effect compared with single-metal organic framework nanoenzymes. Cu-hemin-MOF catalyzes hydrogen peroxide (H2O2) to produce hydroxyl radicals (â¢OH), which oxidizes the chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxidized TMB (oxTMB). The absorbance change is at 650 nm. The content of AOZ in animal food can be quickly and accurately determined by changes in absorbance. The linear range of the colorimetric biosensor for detecting FZD was 0.01 ~ 62.52 ng/mL, and the limit of detection was as low as 0.01 ng/mL. The recovery of spikes samples was in the range 94.2-108.0 % and reproducibility was less than 4.8%. In addition, the cross-reaction rate was less than 0.1% when detecting other metabolites except AOZ, indicating that the sensor has good applicability and specificity. This study not only provides a better understanding of the relationship between the dispersion of nanoenzymes and enzyme-like activity but also offers a general method for detecting antibiotics using the nanoenzyme colorimetric method.
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Colorimetría , Cobre , Furazolidona , Hierro , Límite de Detección , Estructuras Metalorgánicas , Colorimetría/métodos , Cobre/química , Furazolidona/análisis , Furazolidona/química , Estructuras Metalorgánicas/química , Hierro/química , Bencidinas/química , Peróxido de Hidrógeno/química , Animales , Técnicas Biosensibles/métodos , Inmunoensayo/métodos , CatálisisRESUMEN
Toxic intermediates in food caused by chloramphenicol (CP) and furazolidone (FZ) have gained interest in research toward their detection. Hence, fast, reliable, and accurate detection of CP and FZ in food products is of utmost importance. Here, a novel molybdenum disulfide-connected carbon nanotube aerogel/poly (3,4-ethylenedioxythiophene) [MoS2/CNTs aerogel/PEDOT] nanocomposite materials are constructed and deposited on the pretreated carbon paste electrode (PCPE) by a facile eletropolymerization method. The characterization of MoS2/CNTs aerogel/PEDOT nanocomposite was analyzed by scanning electron microscopy (SEM), cyclic voltammetry, and differential pulse voltammetry. The modified MoS2/CNTs aerogel/PEDOT nanocomposite has improved sensing characteristics for detecting CP and FZ in PBS solution. For this work, we have studied various parameters like electrocatalytic activity, the effect of scan rates, pH variation studies, and concentration variation studies. Under optimum conditions, the modified electrode exhibited superior sensing ability compared to the bare and pretreated CPE. This improvement in electrocatalytic activity can be the higher conductivity, larger surface area, increased heterogeneous rate constant, and presence of more active sites in the MoS2/CNTs aerogel/PEDOT nanocomposite. The modified electrode demonstrated distinct electrochemical sensing toward the individual and simultaneous analysis of CP and FZ with a high sensitivity of 0.701 µA. µM-1 .cm-2 for CP and 0.787 µA. µM-1 .cm-2 for FZ and a low detection limit of 3.74 nM for CP and 3.83 nM for FZ with good reproducibility, repeatability, and interferences. Additionally, the prepared sensor effectively detects CP and FZ in food samples (honey and milk) with an acceptable recovery range and a relative standard deviation below 4%.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Cloranfenicol , Disulfuros , Técnicas Electroquímicas , Contaminación de Alimentos , Furazolidona , Molibdeno , Nanocompuestos , Nanotubos de Carbono , Polímeros , Cloranfenicol/análisis , Furazolidona/análisis , Nanocompuestos/química , Nanotubos de Carbono/química , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Contaminación de Alimentos/análisis , Polímeros/química , Disulfuros/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Molibdeno/química , Antibacterianos/análisis , Límite de Detección , Leche/químicaRESUMEN
BACKGROUND AND AIM: After three treatment failures, Helicobacter pylori infection is deemed refractory as antibiotic treatment options become significantly limited. This study evaluated the efficacy and safety of a 14-day modified concomitant therapy for managing refractory H. pylori infection. METHODS: Patients who had failed to respond to three or more rounds of H. pylori therapies were recruited for this study. They received a 14-day modified concomitant therapy, including esomeprazole 40 mg, amoxicillin 1000 mg, and furazolidone 100 mg twice daily and tetracycline 500 mg four times daily. Demographic data, adverse events, and patient compliance were recorded. The presence of H. pylori was reevaluated 6 weeks following treatment. Eradication rate was assessed as the primary outcome. RESULTS: Overall, 59 participants received the 14-day modified concomitant therapy. In the intention-to-treat and per-protocol analyses, the eradication rate was 84.7% (50/59) and 89.3% (50/56), respectively. H. pylori was successfully isolated from 75.0% (12/16) of patients. The resistance rate of H. pylori to metronidazole, levofloxacin, and clarithromycin was 91.7% (11/12), 58.3% (7/12), and 50.0% (6/12), respectively. Resistance to amoxicillin, furazolidone, or tetracycline was not observed. The frequency of adverse events was 35.6% (21/59), with no serious adverse events reported. CONCLUSION: The 14-day modified concomitant therapy appears to be appropriate for refractory H. pylori infection and is particularly promising for the Chinese population. A randomized controlled trial is warranted to verify its efficacy, especially in the current environment of increasing antibiotic resistance.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/etiología , Proyectos Piloto , Furazolidona/efectos adversos , Quimioterapia Combinada , Antibacterianos , Amoxicilina , Metronidazol , Claritromicina/efectos adversos , Resultado del TratamientoRESUMEN
The common utilization of antimicrobial agents in medicine and veterinary creates serious problems with multidrug resistance spreading among pathogens. Bearing this in mind, wastewaters have to be completely purified from antimicrobial agents. In this context, a dielectric barrier discharge cold atmospheric pressure plasma (DBD-CAPP) system was used in the present study as a multifunctional tool for the deactivation of nitro-based pharmacuticals such as furazolidone (FRz) and chloramphenicol (ChRP) in solutions. A direct approach was applied to this by treating solutions of the studied drugs by DBD-CAPP in the presence of the ReO4- ions. It was found that Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), generated in the DBD-CAPP-treated liquid, played a dual role in the process. On the one hand, ROS and RNS led to the direct degradation of FRz and ChRP, and on the other hand, they enabled the production of Re nanoparticles (ReNPs). The produced in this manner ReNPs consisted of catalytically active Re+4, Re+6, and Re+7 species which allowed the reduction of -NO2 groups contained in the FRz and ChRP. Unlike the DBD-CAPP, the catalytically enhanced DBD-CAPP led to almost FRz and ChRP removals from studied solutions. The catalytic boost was particularly highlighted when catalyst/DBD-CAPP was operated in the synthetic waste matrix. Re-active sites in this scenario led to the facilitated deactivation of antibiotics, achieving significantly higher FRz and ChRP removals than DBD-CAPP on its own.
Asunto(s)
Antiinfecciosos , Gases em Plasma , Renio , Antibacterianos/farmacología , Especies Reactivas de Oxígeno , Gases em Plasma/química , Cloranfenicol , Furazolidona , Presión AtmosféricaRESUMEN
BACKGROUND: Furazolidone is a nitrofuran antimicrobial agent used in the treatment of bacterial and protozoal infections. Hypersensitivity to furazolidone is rarely reported and only eight cases have been documented in English since 1967. OBJECTIVES: To report a 24-year-old man who developed exanthematous drug eruptions in general and swelling sensation of the hands after first dose of oral administration of medicines for Helicobacter pylori infection 7 h later, who was finally confirmed with delayed-type IV allergic reaction to furazolidone by provocation tests. And to review the existing literature. METHODS: Thorough clinical examination, prick, intradermal, and patch tests, drug provocation tests were performed in the patient. RESULTS: Skin tests of all used drugs were negative. Drug provocation tests to furazolidone resulted to be positive. CONCLUSIONS: Clinicians should be aware that furazolidone may induce delayed-type allergic reactions; diagnostic approaches should be taken to identify the responsible drug when multiple medications were used concurrently.
Asunto(s)
Dermatitis Alérgica por Contacto , Hipersensibilidad a las Drogas , Infecciones por Helicobacter , Helicobacter pylori , Masculino , Humanos , Adulto Joven , Adulto , Furazolidona , Infecciones por Helicobacter/complicaciones , Dermatitis Alérgica por Contacto/complicaciones , Hipersensibilidad a las Drogas/diagnóstico , AntibacterianosRESUMEN
BACKGROUND: First-line therapy does not always provide a high level of Helicobacter pylori eradication due to the increase of H. pylori resistance to antibiotics; therefore, it remains necessary to identify the most effective rescue treatments. The purpose of this study was to evaluate the efficacy and safety of empirical H. pylori furazolidone-containing regimens. MATERIALS AND METHODS: Adult H. pylori infected patients empirically treated with furazolidone-containing eradication regimens were registered in an international, prospective, multicenter non-intervention European registry on H. pylori management (Hp-EuReg). Data were collected at AEG-REDCap e-CRF from 2013 to 2021 and the quality was reviewed. Modified intention-to-treat (mITT) effectiveness analyses were performed. RESULTS: Overall 106 patients received empirical furazolidone-containing therapy in Russia. Furazolidone was prescribed in a sequential scheme along with amoxicillin, clarithromycin and a proton pump inhibitor in 68 (64%) cases, triple regimens were prescribed in 28 (26%) patients and quadruple regimens in 10 (9.4%). Treatment duration of 7 days was assigned to 2 (1.9%) patients, 10-day eradication therapy in case of 80 (75%) and 14 days - in 24 (23%) patients. Furazolidone was mainly used in first- (79%) and second-line (21%) regimens. The methods used to diagnose H. pylori infection were: histology (81%), stool antigen test (64%), 13C-urea breath test (6.6%), and rapid urease test (1.9%). The mITT effectiveness of sequential therapy was 100%; 93% with the triple therapy and 75.5% with quadruple therapy. Compliance was reported in 98% of cases. Adverse events were revealed in 5.7% of patients, mostly nausea (3.8%). No serious adverse events were reported. CONCLUSION: Furazolidone containing eradication regimens appear to be an effective and safe empirical therapy in Russia.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Adulto , Humanos , Furazolidona/efectos adversos , Estudios Prospectivos , Quimioterapia Combinada , Antibacterianos/efectos adversos , Amoxicilina/efectos adversos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/diagnóstico , Inhibidores de la Bomba de Protones/efectos adversos , Resultado del Tratamiento , Federación de Rusia/epidemiología , Sistema de RegistrosRESUMEN
BACKGROUND: Antibiotic resistance emerges as a major issue for Helicobacter pylori (H. pylori) treatment. High-dose dual therapy has recently shown encouraging results in H. pylori eradication, but it has yet to be validated in this H. pylori highly infected area; it is also not known if this concept can be extended to antibiotics other than amoxicillin, and factors that affect the eradication. We investigate if rabeprazole plus amoxicillin or furazolidone regimens could be a first-line therapy for H. pylori eradication, and factors that affect the curing rate. METHODS: This is a single-center, prospective, open-label, randomized-controlled trial. Naive patients (n=292) were randomly treated with bismuth-containing quadruple therapy (BQT), rabeprazole plus amoxicillin (RADT), or furazolidone (RFDT) groups. RADT and FADT use three times daily regimens. H. pylori diagnosis and eradication were determined and confirmed by 13 C-urea breath test. RESULTS: In per-protocol (PP) analysis, H. pylori eradication rate was 91.2% in BQT group, 89.6% in RADT, and 51.0% in RFDT group. In intention-to-treat (ITT) analysis, infection was eradicated in 86.7% of patients in BQT group, 85.8% in RADT, and 48.1% in RFDT groups, respectively. Noninferiority was confirmed between BQT and RADT groups. The incidence of side effects in BQT group was significantly higher than that in RADT group. Successful eradication was associated with lower body surface area (BSA) and low body mass index (BMI) in BQT group. Smoking and high BSA index reduced H. pylori eradication rate in RADT group. CONCLUSIONS: Rabeprazole-amoxicillin dual therapy is equally effective to the bismuth-containing quadruple therapy for H. pylori eradication with fewer side effects and saves use of one antibiotic per each treatment. Successful eradication is also associated with low BSA and non-smoking condition, which deserves future stratified analysis for refinement and optimization.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Amoxicilina/farmacología , Amoxicilina/uso terapéutico , Antibacterianos , Bismuto , Quimioterapia Combinada , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Estudios Prospectivos , Rabeprazol/uso terapéutico , Resultado del TratamientoRESUMEN
In this work, the hydrothermally synthesized of BiVO4@MoS2 hierarchical nano-heterojunction composite is employed as a novel electrocatalyst for electrochemical sensing of Furazolidone (FZE) drug by modifying the glassy carbon electrodes (GCE). The Raman spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and transmission electron microscopy are used to thoroughly investigate the functional groups, vibrational modes, crystal structure, elemental composition and surface topography of the heterojunction composite. The physical characterization results revealed the successful construction of 1D-2D BiVO4@MoS2 hierarchical nano-heterojunction composite. When these unique architectures are reinforced on GCE surface, we achieved an enhanced electroactive surface area of 0.154 cm2. The electrochemical performance of 1D-2D BiVO4@MoS2 is examined though cyclic voltammetry and differential pulse voltammetry (DPV) analysis. The BiVO4@MoS2 composites exhibited an excellent electrocatalytic activity in sensing of FZE with superior linear detection ranges of 0.01-14 and 14-614 µM. The limit of detection (LOD) of the BiVO4@MoS2 based sensor is determined to be 2.9 nM which is far superior than other reported FZE sensors. Consequently, it is evident from the investigation that the BiVO4@MoS2 based FZE sensor can be recommended for analyzing real time samples like human urine and blood serum with appreciable recovery.
Asunto(s)
Furazolidona , Molibdeno , Técnicas Electroquímicas/métodos , Electrodos , Humanos , Límite de Detección , Molibdeno/químicaRESUMEN
BACKGROUND: Trueperella pyogenes and Pseudomonas aeruginosa are two important bacterial pathogens closely relating to the occurrence and development of forest musk deer respiratory purulent disease. Although T. pyogenes is the causative agent of the disease, the subsequently invaded P. aeruginosa will predominate the infection by producing a substantial amount of quorum-sensing (QS)-controlled virulence factors, and co-infection of them usually creates serious difficulties for veterinary treatment. In order to find a potential compound that targets both T. pyogenes and P. aeruginosa, the antibacterial and anti-virulence capacities of 55 compounds, which have similar core structure to the signal molecules of P. aeruginosa QS system, were tested in this study by performing a series of in vitro screening experiments. RESULTS: We identified that furazolidone could significantly reduce the cell densities of T. pyogenes in mono-culture or in the co-culture with P. aeruginosa. Although the growth of P. aeruginosa could also be moderately inhibited by furazolidone, the results of phenotypic identification and transcriptomic analysis further revealed that sub-inhibitory furazolidone had remarkable inhibitory effect on the biofilm production, motility, and QS system of P. aeruginosa. Moreover, furazolidone could efficiently protect Caenorhabditis elegans models from P. aeruginosa infection under both fast-killing and slow-killing conditions. CONCLUSIONS: This study reports the antibacterial and anti-virulence abilities of furazolidone on T. pyogenes and P. aeruginosa, and provides a promising strategy and molecular basis for the development of novel anti-infectious drugs to dealing with forest musk deer purulent disease, or other diseases caused by T. pyogenes and P. aeruginosa co-infection.
Asunto(s)
Ciervos , Pseudomonas aeruginosa , Animales , Antibacterianos/farmacología , Biopelículas , Ciervos/microbiología , Furazolidona/farmacología , Percepción de Quorum , Virulencia , Factores de VirulenciaRESUMEN
BACKGROUND AND AIM: The increase in antibiotic resistance makes the eradication of Helicobacter pylori more difficult. Considering the limitations of the application of susceptibility-guided therapy, it is important to find an effective empirical regimen. The aim of the study is to compare the efficacy, safety, and cost-effectiveness of clarithromycin-based bismuth-containing quadruple therapy (C-BQT) and furazolidone-based bismuth-containing quadruple therapy (F-BQT) in naïve H. pylori positive patients. METHODS: This was an open-label, randomized controlled, crossover trial. The trial comprised two phases. In C-F group, patients received C-BQT in the first phase; those who were still positive for H. pylori infection after the first phase entered the second phase to receive F-BQT as rescue treatment. In F-C group, patients were treated with F-BQT firstly and rescued with C-BQT. RESULTS: As first-line treatments, the eradication rates of C-BQT and F-BQT were 89.7% (157/175) and 92.0% (161/175) (P = 0.458) in intention-to-treat analysis and 93.4% (156/167) and 95.8% (161/168) (P = 0.327) in per-protocol analysis, respectively. The cumulative eradication rates of the C-F group and the F-C group were both 94.3% in intention-to-treat analysis (P = 1.000). Cost-effectiveness indexes of F-BQT and C-BQT were 0.54 and 1.24 in first-line treatments. Frequencies of adverse events in F-BQT and C-BQT had no differences (36.0% in C-BQT vs 32.6% in F-BQT, P = 0.499). CONCLUSIONS: Furazolidone-based bismuth-containing quadruple therapy should be preferred for its excellent cost-effectiveness and acceptable safety.
Asunto(s)
Claritromicina , Furazolidona , Infecciones por Helicobacter , Helicobacter pylori , Antibacterianos/efectos adversos , Antibacterianos/economía , Bismuto/efectos adversos , Bismuto/economía , Claritromicina/efectos adversos , Claritromicina/economía , Análisis Costo-Beneficio , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/economía , Furazolidona/efectos adversos , Furazolidona/economía , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/aislamiento & purificación , Humanos , Resultado del TratamientoRESUMEN
Furazolidone (FZD) is a widely used drug in human and veterinary medicine, and has antibacterial and antiprotozoal action. Although it is widely used as a therapy in various pathological conditions, studies on the efficacy of FZD associated with immune responses are still limited. In this review, we seek to describe which immunopharmacological responses are caused by the administration of FZD. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review of clinical trials and in vitro and in vivo experimental studies was carried out, which resulted in 943 papers, of which 35 were considered eligible and, of these 35, 4 were selected for analysis. The studies listed indicated that administration of FZD can modulate pro- or anti-inflammatory pathways, with a probable increase in the expression of reactive oxygen species and a modulation of apoptotic pathways.
Asunto(s)
Inmunidad Adaptativa/inmunología , Antiinfecciosos Locales/farmacología , Apoptosis/inmunología , Furazolidona/farmacología , Inmunidad Innata/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics.
Asunto(s)
Antibacterianos/química , Furazolidona/química , Nitrofurantoína/química , Antibacterianos/farmacocinética , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Teoría Funcional de la Densidad , Furazolidona/farmacocinética , Espectrometría de Masas , Estructura Molecular , Nitrofurantoína/farmacocinética , Solubilidad , Termodinámica , TermogravimetríaRESUMEN
BACKGROUND: Antimicrobial combinations have been proven as a promising approach in the confrontation with multi-drug resistant bacterial pathogens. In the present study, we identify and characterize a synergistic interaction of broad-spectrum nitroreductase-activated prodrugs 5-nitrofurans, with a secondary bile salt, Sodium Deoxycholate (DOC) in growth inhibition and killing of enterobacteria. RESULTS: Using checkerboard assay, we show that combination of nitrofuran furazolidone (FZ) and DOC generates a profound synergistic effect on growth inhibition in several enterobacterial species including Escherichia coli, Salmonella enterica, Citrobacter gillenii and Klebsiella pneumoniae. The Fractional Inhibitory Concentration Index (FICI) for DOC-FZ synergy ranges from 0.125 to 0.35 that remains unchanged in an ampicillin-resistant E. coli strain containing a ß-lactamase-producing plasmid. Findings from the time-kill assay further highlight the synergy with respect to bacterial killing in E. coli and Salmonella. We further characterize the mechanism of synergy in E. coli K12, showing that disruption of the tolC or acrA genes that encode components of multidrug efflux pumps causes, respectively, a complete or partial loss, of the DOC-FZ synergy. This finding indicates the key role of TolC-associated efflux pumps in the DOC-FZ synergy. Overexpression of Nitric Oxide-detoxifying enzyme Hmp results in a three-fold increase in FICI for DOC-FZ interaction, suggesting a role of nitric oxide in the synergy. We further demonstrate that DOC-FZ synergy is largely independent of NfsA and NfsB, the two major activation enzymes of the nitrofuran prodrugs. CONCLUSIONS: This study is to our knowledge the first report of nitrofuran-deoxycholate synergy against Gram-negative bacteria, offering potential applications in antimicrobial therapeutics. The mechanism of DOC-FZ synergy involves FZ-mediated inhibition of TolC-associated efflux pumps that normally remove DOC from bacterial cells. One possible route contributing to that effect is via FZ-mediated nitric oxide production.
Asunto(s)
Ácido Desoxicólico/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Enterobacteriaceae/crecimiento & desarrollo , Furazolidona/farmacología , Proteínas de la Membrana Bacteriana Externa/genética , Citrobacter/efectos de los fármacos , Citrobacter/crecimiento & desarrollo , Sinergismo Farmacológico , Enterobacteriaceae/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Lipoproteínas/genética , Proteínas de Transporte de Membrana/genética , Viabilidad Microbiana/efectos de los fármacos , Profármacos/farmacología , Salmonella enterica/efectos de los fármacos , Salmonella enterica/crecimiento & desarrolloRESUMEN
The interaction between DNA and furazolidone/furacillin was investigated using various analytical techniques including spectroscopy and electroanalysis and molecular modelling. With the aid of acridine orange (AO), the fluorescence lifetimes of DNA-AO, DNA-furazolidone/furacillin-AO remained almost the same, which proved that the ground state complex was formed due to furazolidone/furacillin binding with DNA. Circular dichroism spectra and Fourier transform infrared spectroscopy showed that the second structure of DNA changed. Viscosity experiments presented that relative viscosity of DNA was increased with the increasing concentrations of furazolidone and almost unchanged for furacilin. In addition, the results of melting temperature (Tm ), ionic strength, site competition experiments, cyclic voltammetry, and molecular docking all proved the intercalation binding mode for furazolidone and groove binding mode for furacilin. The binding constants (Ka ) obtained from Wolfe-Shimmer equation were calculated as 3.66 × 104 L mol-1 and 3.95 × 104 L mol-1 for furazolidone-DNA and furacilin-DNA, respectively.
Asunto(s)
ADN/química , Técnicas Electroquímicas , Furazolidona/química , Simulación del Acoplamiento Molecular , Nitrofurazona/química , Sitios de Unión , Dicroismo Circular , Espectroscopía Infrarroja por Transformada de Fourier , ViscosidadRESUMEN
The global spread of multidrug-resistant enterobacteria warrants new strategies to combat these pathogens. One possible approach is the reconsideration of "old" antimicrobials, which remain effective after decades of use. Synthetic 5-nitrofurans such as furazolidone, nitrofurantoin, and nitrofurazone are such a class of antimicrobial drugs. Recent epidemiological data showed a very low prevalence of resistance to this antimicrobial class among clinical Escherichia coli isolates in various parts of the world, forecasting the increasing importance of its uses to battle antibiotic-resistant enterobacteria. However, although they have had a long history of clinical use, a detailed understanding of the 5-nitrofurans' mechanisms of action remains limited. Nitrofurans are known as prodrugs that are activated in E. coli by reduction catalyzed by two redundant nitroreductases, NfsA and NfsB. Furazolidone, nevertheless, retains relatively significant antibacterial activity in the nitroreductase-deficient ΔnfsA ΔnfsBE. coli strain, indicating the presence of additional activating enzymes and/or antibacterial activity of the unreduced form. Using genome sequencing, genetic, biochemical, and bioinformatic approaches, we discovered a novel 5-nitrofuran-activating enzyme, AhpF, in E. coli The discovery of a new nitrofuran-reducing enzyme opens new avenues for overcoming 5-nitrofuran resistance, such as designing nitrofuran analogues with higher affinity for AhpF or screening for adjuvants that enhance AhpF expression.
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Escherichia coli/enzimología , Nitrorreductasas/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Furazolidona/química , Furazolidona/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Nitrofuranos/metabolismo , Nitrofuranos/farmacología , Nitrofurantoína/química , Nitrofurantoína/farmacología , Nitrofurazona/química , Nitrofurazona/farmacología , Nitrorreductasas/genética , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismoRESUMEN
BACKGROUND & AIMS: The eradication rate of Helicobacter pylori (H pylori) has decreased largely because of the antibiotic resistance. We aimed to evaluate the effectiveness and safety of furazolidone-containing quadruple regimens for H pylori eradication. METHODS: This was an observational study of furazolidone-containing quadruple regimens for H pylori infection in real-world settings. Data sets were collected from the medical records and telephone interviews of patients referred to a specialist clinic for suspected H pylori reinfection from January 1, 2015, to January 1, 2018, at the First Affiliated Hospital of Nanchang University. Main outcome measures were the eradication rate and adverse reactions during medication. RESULTS: Among 584 patients with H pylori infection that met the inclusion criteria, 561 (96.1%) were treated for the first time, 19 (3.3%) had one, and 4 (0.5%) had two or more prior to furazolidone-containing quadruple regimens. The eradication rates for 10-day and 14-day regimens were 93.7% (95% CI: 91.5%-95.9%) vs 98.2% (95% CI: 95.6%-99.3%), respectively (P = 0.098). Adverse drug reactions occurred in 8.2% (48/584) with abdominal discomfort being the most common symptom. Overall adverse events with 10-day regimens were lower than 14-day regimens (6.1% vs 17.4%, P < 0.001). Logistic regression analysis indicated that poor adherence (adjusted odds ratio [AOR] = 46.5, 95% CI: 9.7-222.4) was correlated with failed eradication. Adverse drug reactions during medication were related to smoking and tobacco status, alcohol intake history, regimens combined with tetracycline, and poor adherence (all P < 0.05). CONCLUSIONS: Furazolidone-containing quadruple regimens proved both safe and highly effective in a real-world setting.
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Furazolidona/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Adulto , Anciano , Femenino , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/fisiología , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
Antibiotic resistance is a major cause of Helicobacter pylori (H. pylori) treatment failures. Because the resistance rate of H. pylori to furazolidone is low, we aimed to assess the efficacy and safety of furazolidone. We searched the PubMed, Web of Science, Cochrane Library, and Embase databases and included randomized controlled trials (RCT) that either compared furazolidone to other antibiotics or changed the administered dose of furazolidone. A total of 18 articles were included in the meta-analysis. According to the intention-to-treat (ITT) analysis, the total eradication rates of furazolidone-containing therapy were superior to those of other antibiotic-containing therapies (relative risk [RR] 1.07, 95% confidence interval [CI] 1.01-1.14) (13 RCTs). Specifically, the eradication rates of furazolidone-containing therapy were better than those for metronidazole-containing therapy (RR 1.10, 95% CI: 1.01-1.21 for ITT). The eradication rate of furazolidone-containing bismuth-containing quadruple therapy was 92.9% (95% CI: 90.7%-95.1%) (PP). In addition, a higher daily dose of furazolidone increased the eradication rate (RR 1.17, 95% CI: 1.05-1.31). And the incidence of some adverse effects, such as fever and anorexia, was higher in the furazolidone group than in the control group, the overall incidences of total side effects and severe side effects showed no significant differences between the groups. Furazolidone-containing treatments could achieve satisfactory eradication rates and did not increase the incidence of total or severe adverse effects, but the incidence of milder side effects, such as fever and anorexia, should be considered when prescribing furazolidone-containing treatments to patients.
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Furazolidona/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Antibacterianos/uso terapéutico , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/patogenicidad , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: The efficacy of Helicobacter pylori (H. pylori) eradication has steadily declined, primarily because of antibiotic resistance. This study aimed to evaluate the efficacy and safety of furazolidone eradication therapies as initial treatments for H. pylori infection. METHODS: A national, multicenter, open-label, randomized controlled trial was performed at 16 sites across 13 provinces in China to evaluate the efficacy and safety of furazolidone-containing therapies for H. pylori infection. Treatment naïve patients were randomly assigned to: esomeprazole 20 mg, bismuth 220 mg, amoxicillin 1000 mg, and furazolidone 100 mg twice daily for 10 and 7 days (FAB 10 and FAB 7; the same therapy without bismuth (FA 10 and FA 7). The primary and secondary outcomes were the eradication rate and regimen safety, respectively. Treatment success was assessed by the 13 C urea breath test at least 4 weeks after treatment completion. RESULTS: Overall, according to intention-to-treat (ITT) analysis, the eradication rates for FAB 10 and FAB 7 were 86.6% (95% confidence interval [CI], 79.9%-93.2%) and 83.6% (95% CI, 76.3%-90.9%) and for FA 10 and FA 7 were 82.4% (95% CI, 74.9%-89.8%) and 77.6% (95% CI, 69.4%-85.8%), respectively. According to per-protocol analysis, the overall eradication rates for FAB 10 and FAB 7 were 94.7% (95% CI, 90.3%-99.1%) and 90.8% (95% CI, 85.1%-96.5%) and for FA 10 and FA 7 were 90.6% (95% CI, 84.9%-96.3%) and 85.1% (95% CI, 78.2%-92.1%), respectively. The overall prevalence of side effects was 8.1%. CONCLUSIONS: Furazolidone-containing therapies, particularly the tested 10-day quadruple therapy, exhibited satisfactory efficacy and safety. This 10-day quadruple therapy represents a promising initial treatment strategy for Chinese patients.