- Covalent protein modification by reactive drug metabolites using online electrochemistry/liquid chromatography/mass spectrometry
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We present a rapid and convenient method to perform and evaluate the covalent protein binding of reactive phase I metabolites. The oxidative metabolism of the drugs paracetamol, amodiaquine, and clozapine is simulated in an electrochemical (EC) flow-through cell, which is coupled online to an LC/MS system. Adduct formation of the reactive metabolites with the proteins β-lactoglobulin A and human serum albumin proceeds in a reaction coil between EC cell and injection system of the HPLC system. The formed drug-protein adducts are characterized with online time-of-flight mass spectrometry, and the modification site is localized using FTICR-mass spectrometry. Due to its simple setup, easy handling, and short analysis times, the method provides an interesting tool for the rapid risk assessment of covalent protein binding as well as for the synthesis of covalent drug-protein adducts in high purity and high yield.
- Lohmann, Wiebke,Hayen, Heiko,Karst, Uwe
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- Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes
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Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO-) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO- and Rhod-ONOO-) for ONOO- through a novel and universally applicable mechanism: ONOO--mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO- can selectively accumulate and react in mitochondria, one of the main sources of ONOO-, with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO- and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO- generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.
- Cheng, Dan,Xu, Wang,Yuan, Lin,Zhang, Xiaobing
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- Acetaminophen binds to mouse hepatic and renal DNA at human therapeutic doses
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Alkylation of DNA by acetaminophen metabolites has been reported previously, but has received little attention, and the biological impact of this alkylation is essentially unknown. In the present study, apparent covalent binding of acetaminophen metabolites to DNA in male ICR mice was observed at levels of 2.0 ± 0.4 to 18.5 ± 5.5 pmol of acetaminophen/mg of DNA in liver and 0.6 ± 0.1 to 26.9 ± 2.6 pmol of acetaminophen/mg of DNA in kidney with doses ranging from 10 to 400 mg/kg. Investigations of the reaction of [3H]-N-acetyl-p-benzoquinone imine (NAPQI) or [ring-14C]NAPQI with DNA in vitro yielded low levels of DNA alkylation. Greater apparent binding of [3H]NAPQI to DNA occurred in reactions containing nuclear proteins, such as by using chromatin or whole nuclei. The binding of NAPQI to purified DNA also was enhanced by the presence of 0.1 mM cysteine, but not by 1.0 mM cysteine. Increased binding of NAPQI to DNA in the presence of cysteine or nuclear protein is in contrast to the effects of alternate sulfhydryls on the binding of NAPQI to proteins, which implies that the mechanisms responsible for binding to DNA may be different than the mechanisms that mediate alkylation of protein. The alkylation of DNA by [ring-14C]NAPQI was enhanced markedly at buffer pH 2O2. Measurable binding was obtained in all systems, but HRP and H2O2 produced binding levels 200-fold greater than was observed with the microsomal systems. The 32P-postlabeling of DNA from acetaminophen-treated mice, and of DNA reacted with acetaminophen, HRP, and H2O2, produced unique spots that were not identical. The present data further support the hypothesis that acetaminophen metabolites bind covalently to DNA and demonstrate that this apparent binding is observed in experimental animals in vivo at doses that mimic therapeutic doses in humans.
- Rogers, Lynette K.,Moorthy, Bhagavatula,Smith, Charles V.
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- Electrochemical performance of a new imidazolium ionic liquid crystal and carbon paste composite electrode for the sensitive detection of paracetamol
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A new ionic liquid crystal (ILC) bearing a biphenyl core and a terminal imidazolium moiety was synthesized which exhibited two enantiotropic smectic A mesophases having a wide phase range. Interestingly one of these mesophases exhibited the features of a biaxial phase. A composite electrode containing the synthesized ILC and carbon paste (CP) was fabricated and employed for the successful electrochemical detection of a clinically important analgesic drug, paracetamol. The ILC-CP composite electrode displayed an enhanced current response due to a versatile combination of properties namely, good ionic conductivity, increased edge-site defects and excellent electrocatalytic activity. The composite electrode responded quickly upon addition of paracetamol and the peak current of anodic oxidation enhanced at lower over potential compared to the carbon paste electrode (CPE). Differential pulse voltammetric (DPV) experiments for the detection of paracetamol yielded acceptable linear range from 0 to 120 μM with a good detection limit of 2.8 μM. Interference test results showed anti-interfering ability in presence of a mixture of interferents. The electrode stability was evaluated from DPV current response and 92.6% current was retained after one month which revealed the excellent stability. The electrode was successfully applied for the direct determination of paracetamol in pharmaceutical formulations.
- Khan, Rajkumar,Mangaiyarkarasi, R.,Pratibha, R.,Premlatha, S.,Umadevi, S.
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- Selective determination of paracetamol and acetylsalicylic acid on electrode modified with a mixed-valent film of ruthenium oxide-ruthenium cyanide
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Catalytic activity exhibited by a mixed-valent film of ruthenium oxideruthenium cyanide deposited on the surface of a glassy-carbon electrode in electrooxidation of paracetamol and acetylsalicylic acid was used to develop a high-sensitivity selective method for determination of these compounds in the case of their joint presence under flow-injection conditions.
- Shaidarova,Gedmina,Chelnokova,Budnikov
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- Ni2P Nanosheets: A High Catalytic Activity Platform for Electrochemical Detection of Acetaminophen
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Accurate determination of acetaminophen concentration is essential for studying the metabolic status of acetaminophen in clinical practice. In this study, nickel phosphide was used for electrochemical detection of acetaminophen for the first time. An electrochemical acetaminophen sensor based on Ni2P nanosheets was successfully constructed and the sensor showed many convincing properties: (a) a good linear range (0.5 μmol/L—4.5 mmol/L); (b) a moderate sensitivity (131.1 μA·mmol–1·L·cm–2); (c) a low detection limit (0.107 μmol/L). In addition, the sensor also showed excellent selectivity, robust stability and reliable repeatability. Further experiments demonstrate that the prepared sensor can be used for quantitative detection of acetaminophen in commercial medical drugs.
- Bai, Liwei,Cao, Xiaowei,Jia, Jianfeng,Jiang, Yimin,Liu, Guoqin,Liu, Xuebo,Lu, Wenbo,Wei, Ming,Wu, Haishun
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- Monitoring analgesic drug using sensing method based on nanocomposite
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This paper reports a rapid, reliable and sensitive electrochemical method for the determination of acetaminophen, a safe analgesic drug. Most methods currently used for therapeutic drug monitoring require a pre-treatment of the sample. Biosensors avoid this kind of drawbacks. A horseradish peroxidase (HRP) was immobilized using core-shell ZrO@Fe3O4 nanoparticles on chitosan hybrid film electrodeposited on the surface of an Au electrode. The surface functionalization of core-shell ZrO@Fe3O4NPs on a chitosan hybrid film was characterized by cyclic voltammetry (CV), scanning electron microscopy (SEM), and electrochemical impedance spectroscopy (EIS). The experimental variables that can affect the acetaminophen amperometric response, such as the pH, temperature and applied potential, have been optimized to perform a selective determination of acetaminophen. An average limit of detection of 0.01 μM (S/N = 3) was obtained. The biosensor was finally applied to the determination of acetaminophen in complex matrices, such as pharmaceutical drugs.
- Narang, Jagriti,Malhotra, Nitesh,Singh, Sandeep,Singh, Gajendra,Pundir
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- Metabolites of acetaminophen trigger Ca2+ release from liver microsomes
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Release of mitochondrial calcium is believed to play a key role in the toxicity of acetaminophen in biological systems. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. The major metabolites of acetaminophen, benzoquinone imine and 1,4-benzoquinone, induced Ca2+ release in isolated rat liver microsomes. The 1,4-benzoquinone-induced release of calcium was suppressed by ryanodine and fully inhibited by reduced glutathione. Concentrations of 1,4-benzoquinone that induced Ca2+ release did not affect the activity of the microsomal Ca2+, Mg2+-APTase. The binding of [3H]ryanodine to liver microsomes, however, was significantly decreased by 1,4-benzoquinone, suggesting a direct interaction of this metabolite with the ryanodine-binding protein (ryanodine receptor). These results suggest that cellular Ca2+ levels may be elevated by acetaminophen by pathways involving, in part, activation of Ca2+ releasing channels such as the ryanodine receptor. Copyright (C) 1999 Elsevier Science Ireland Ltd.
- Stoyanovsky, Detcho A.,Cederbaum, Arthur I.
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- Facile and clean electrochemical synthesis of new acetaminophen derivatives through electrochemical oxidation of acetaminophen in the presence of thiouracil derivatives
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The electrochemical oxidation of acetaminophen (1a) is carried out in the presence of thiouracil derivatives (3a–c), as nucleophiles, in an acetate buffer solution (0.15 M, pH 5) mixed with Dimethylformamide (DMF) using cyclic voltammetry and coulometry under a constant potential. The results obtained indicate that N-acetyl-p-benzoquinone-imine derived from acetaminophen participates in a 1,4-Michael-type addition reaction with thiouracils to form the corresponding acetaminophen derivatives (4a–c) in good yields and with high purities using a facile, catalyst-free, and one-pot electrochemical method using three carbon electrodes in an undivided cell under mild conditions. The products obtained were characterized after purification by IR, 1H NMR, and 13C NMR spectroscopies, and by the elemental analysis method.
- Asghari, Alireza,Ameri, Mohsen,Taghipour, Samira,Ghaderi, Omid
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- Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol
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1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -C(H)3, -C2H5, -iC3H7) have been determined with β-naphthoflavone (βNF)-induced rat liver microsomes and produced reverse type I spectral changes. K(s,app) varied from 0.14 mM for 3,5-diiC3H7-paracetamol to 2.8 mM for paracetamol. 2. All seven analogues underwent rat liver microsomal cytochrome P450-dependent oxidation, as reflected by the formation of GSSG in the presence of GSH. The GSSG-formation was increased in all cases upon pretreatment of rats by β-naphthoflavone (βNF) and was generally decreased upon pretreatment by phenobarbital (PB). 3. Rat liver microsomal cytochrome P450 as well as horseradish peroxidase catalysed the formation of 3,5-disubstituted NAPQI analogues from the corresponding parent compounds, as identified by UV-spectrophotometry of the NAPQI analogues and by GC/MS detection of the following GSH-conjugates: 2-glutathione-S-yl-3,5-dimethyl-1,4-dihydroxybenzene, 2-glutathione-S-yl-3,5-dichloro-paracetamol, and 2-glutathione-S-yl-3,5-dibromo-paracetamol. 4. In liver microsomal (βNF-induced) incubations, apparent K(m) values, as determined for the cytochrome P450 catalysis-dependent oxidation of GSH, for seven 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, iC3H7) varied from 0.07 to 0.64 mM. Paracetamol exhibited an apparent K(m) of 0.73 mM. Apparent V(max) values for the cytochrome P450 catalysis dependent oxidation of GSH varied from 0.66 nmol min-1 mg-1 protein for paracetamol to 3.0 nmol min-1 mg-1 protein for 3,5-dimethyl-paracetamol.
- Bessems,Te Koppele,Van Dijk,Van Stee,Commandeur,Vermeulen
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- Simultaneous determination of ciprofloxacin and paracetamol by adsorptive stripping voltammetry using copper zinc ferrite nanoparticles modified carbon paste electrode
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This work presents the development of an electrochemical sensor in the form of a copper zinc ferrite nanoparticle modified carbon paste electrode (CZF-CME) for the simultaneous determination of ciprofloxacin (CIP) and paracetamol (PA) using adsorptive stripping differential pulse voltammetry. The results indicate that the modified electrode exhibited enhancement of the oxidation peak current and shift in the oxidation potential to lower values in comparison with plain carbon paste electrode (CPE) for ciprofloxacin and paracetamol. The electrochemical performances of the modified electrode were investigated by cyclic voltammetry, chronocoulometry and electrochemical impedance spectroscopy, indicating the greater affinity of CIP and PA at the CZF-CME than at PCPE. Under the optimized conditions, the linear working ranges are from 9.09 × 10-7 M to 4.70 × 10-3 M and 1.85 × 10-7 M to 4.76 × 10-4 M for CIP and PA respectively. The detection limits (S/N = 3) of 2.58 × 10-9 M and 8.85 × 10-8 M for CIP and PA respectively were obtained when taken together. The CZF-CME showed relatively high sensitivity, selectivity, stability and the proposed method was successfully used for individual and simultaneous determination of ciprofloxacin and paracetamol in pharmaceutical formulations, serum and urine samples.
- Kingsley, Mal Phebe,Kalambate, Pramod K.,Srivastava, Ashwini K.
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- MWCNT-CTAB modified glassy carbon electrode as a sensor for the determination of paracetamol
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An electrochemical sensor for the sensitive detection of paracetamol (PCM) was developed by constructing a glassy carbon electrode (GCE) modified with multiwalled carbon nanotube-cetyltrimethyl ammonium bromide (MWCNT-CTAB). Modification improves the redox kinetics of PCM with increased current intensity. A similar modification at CTAB modified GCE did not result in an impressive charge transfer. The detection limit of PCM was determined from a differential pulse voltammetric (DPV) study and found to be 4.82 × 10-9 M with a linear dynamic range of 4.0 × 10-7 M to 4.0 × 10-6 M. The interference studies showed that the modified electrode exhibits excellent selectivity in the presence of a large excess of interferents and the response is fast, stable, reliable, resistant to biofouling and can be applied for real sample analysis in medical, pharmaceutical and biotechnological sectors. Kinetic parameters were determined using electrochemical approaches. The practical analytical application of this electrode was demonstrated by measurement of the PCM content in a PYREMOL 650 tablet and real sample analysis.
- Gowda, Jayant I.,Gunjiganvi, Danavva G.,Sunagar, Nagaveni B.,Bhat, Manjushree N.,Nandibewoor, Sharanappa T.
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- GdTiO3 perovskite modified graphene composite for electrochemical simultaneous sensing of Acetaminophen and Dopamine
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A novel electrochemical biosensor was developed using GdTiO3 (GTO) perovskite prepared by sol-ge l(S) and hydrothermal (H) methods and decorated on few layered graphene for simultaneous sensing and quantification of dopamine (DA) and acetaminophen (ACE). The physical and structural characterization of the perovskites and composites were done using XRD, Raman, FTIR, XPS, and TEM analysis. Electrochemical characterization indicates higher activity for the GTO(S)-Gr composite modified electrode than the individual graphene, GTO(S) and GTO(H) component modified electrodes towards DA and ACE sensing. Simultaneous sensing in physiological buffer under optimized conditions exhibited wide linear ranges from 72 nM to 1.5 μM with lowest detection limit (LOD) 96.89 nM for DA and 50 nM to 1.5 μM with LOD 58.85 nM for ACE. The estimated sensitivity values are 3.357 × 10?5 A/nM and 2.177 × 10?5 A/nM, respectively for DA and ACE being higher than that of the literature reported for the graphene based metal oxide and perovskite sensors. The sensor showed high selectivity towards DA and ACE in the presence of co-interfering components like ascorbic acid, uric acid which may oxidize at the same potential.The binary composite was validated for DA and ACE sensing in practical applications using blood serum, tablet and urine samples and observed good signal recovery. The fabricated sensor was stable and showed good reproducibility.
- Anancia Grace, Arockiajawahar,Dharuman, Venkataraman,Hahn, Jong Hoon
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- Kinetic insights on the oxidation of acetaminophen and caffeine by a Mn(IV)3 complex
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The kinetics of the oxidation reactions of APAP and Cafn by a Mn(IV)-oxidant, [MnIV3(μ-O)4(phen)4(H2O)2]4+ (1) has been studied at room temperature. Under the acidic reaction condition ([H+] = 0.2–1.0?M), both APAP and Cafn exist in equilibrium with their conjugate acids APAPH+ and CafnH+ and each of the species acts as the potential reductants. Kinetic observations reveal that the observed rate constant, ko, values increase with the increase in media acidity and the ionic strength, I. The second-order rate-constant values for oxidizing the protonated forms of the two reductants (APAPH+ and CafnH+) were evaluated to be 6.04 ± 0.29 and 0.18 ± 0.01?M?1?s?1, respectively. Overall, under acid media, Mn(IV)-complex efficiently oxidizes APAP to a mixture of benzoquinone and acetamide (or, to quinone oxime and acetic acid) and Cafn to 1,3,7-trimethyluric acid.
- Das, Ranendu Sekhar,Singh, Bula
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p. 565 - 573
(2021/09/09)
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- Organic-Inorganic Hybrid Cerium-Encapsulated Selenotungstate including Three Building Blocks and Its Electrochemical Detection of Dopamine and Paracetamol
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A novel organic-inorganic hybrid cerium-encapsulated selenotungstate comprising three polyoxotungstate building units Na16H6{[Ce3W4O10(H2O)9(CH3COO)3]2(Se2W7O30)(B-α-SeW9O33)4}·(C5H8NBO3)·119H2O (1) was synthesized by the portfolio approach of an in situ self-assembly reaction and step-by-step synthesis. The hybrid polyoxoanion of 1 is constructed from an acetate-coordinated heterometallic {[(Ce3W4O10)(H2O)9(CH3COO)3]2(Se2W7O30)}10+ core encompassing four trilacunary [B-α-SeW9O33]8- subunits. Interestingly, the heterometallic core contains a remarkable [Se2W7O30]10- building block in which seven WVI atoms form a W7 plane and two SeIV atoms are situated on two opposite faces of the W7 plane. In addition, the electrochemical performances of the 1?CFMCN composite (CFMCN: carboxyl-functionalized multiwalled carbon nanotube) were investigated. The 1?CFMCN/GCE (GCE: glass carbon electrode) sensor demonstrates a promising potential in electrochemically sensing dopamine (DPA) or paracetamol (PCM) or even simultaneously detecting DPA and PCM with low limits of 0.053 μM for DPA and 2.03 μM for PCM over a wide linear range at high sensitivity.
- Chen, Lijuan,Jiang, Jun,Liu, Guoping,Liu, Lulu,Wang, Dan,Zhang, Yan,Zhao, Junwei
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supporting information
p. 15355 - 15364
(2020/11/02)
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- 3D multiporous Co,N co-doped MoO2/MoC nanorods hybrids as improved electrode materials for highly sensitive simultaneous determination of acetaminophen and 4-aminophenol
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3D multiporous Co, N co-doped MoO2/MoC (3D Co,N-MoO2/MoC) nanorods hybrids were successfully synthesized via carburizing core-shell ZIF-67-cladded MoO3 nanorods precursor at high temperature. As-fabricated Co,N-MoO2/MoC nanorods coated glassy carbon electrodes (GCE) was demonstrated to possess superior electrocatalytic activity for the electro-oxidation of acetaminophen (AC) and 4-aminophenol (4-AP). Such excellent electrochemical performance was largely attributed to the synergistic effect of the unique multiporous structure, the optimal component and abundant active sites of the nanorods. The corresponding electrode reaction mechanisms were studied in detail in this article. Under optimal conditions, the linear detection ranges were 0.05–200.0 μmol/L for AC and 0.05–140.0 μmol/L for 4-AP, respectively, with the low detection limits of 0.013 μmol/L and 0.012 μmol/L. Furthermore, the 3D Co,N-MoO2/MoC/GCE revealed excellent sensitivity, good reproducibility, stability and anti-interference ability. The developed electrode was evaluated towards the detecting AC and 4-AP in biological fluids, environment water and pharmaceutical formulations with satisfactory recovery, which had a broad application prospect.
- Dong, Yuanyuan,Zhou, Min,Zhang, Lei
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- Preparation of β-cyclodextrin functionalized reduced graphene oxide: Application for electrochemical determination of paracetamol
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β-Cyclodextrin functionalized reduced graphene oxide (β-CD/RGO) was successfully prepared using a simple wet chemical method. The β-CD/RGO nanohybrid was characterized by UV-vis spectroscopy, FTIR, Raman spectroscopy, TEM and SEM. The results confirmed that β-CD had effectively covered the RGO surface. The β-CD/RGO nanohybrid modified glassy carbon electrode was employed for the sensitive electrochemical determination of paracetamol. Cyclic voltammetry measurements indicated that β-CD/RGO could significantly enhance the electrochemical response of paracetamol due to the outstanding electronic properties of RGO sheets and the high supramolecular recognition and enrichment capability of β-CD. The experimental factors were investigated and optimized. Under optimized conditions, the amperometric oxidation currents of paracetamol were linearly proportional to the concentration in the range of 0.01 to 0.8 mM with a detection limit of 2.3 μM (S/N = 3). Furthermore, the proposed sensor exhibited an excellent anti-interference property and acceptable reproducibility.
- Fu, Li,Lai, Guosong,Yu, Aimin
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p. 76973 - 76978
(2015/09/28)
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- Modified glassy carbon electrode with AuNPs using cis-[RuCl(dppb)(bipy)(4- vpy)]+ as crossed linking agent
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This work links aspects of non-covalent interaction among gold nanoparticles (AuNPs) and ruthenium complexes, which were used to modify the surface of the glassy carbon electrode (GCE), without the necessity of a sulfur substrate with a covalent bond between gold-sulfur (Au-S), to keep the AuNPs onto the surface of the electrode. The AuNPs were synthesized by the method of encapsulation by citrate conferring on them a negative charge. The ruthenium complex [RuCl(dppb)(bipy)(4-vpy]+ was synthesized by ligand exchange in its coordination sphere, giving it a positive charge. A thin film of [RuCl(dppb)(bipy)(4-vpy)]+ was generated onto the surface of glassy carbon electrode (GCE), using cyclic voltammetry, under potential cycling between -0.9 and -2.4 V, to produce the CGE-Ru+ electrode. Afterward, the GCE-Ru+ electrode was kept in a colloidal suspension of AuNPs for 1 h to incorporate them onto the surface of GCE-Ru+ by electrostatic interaction. The resulting electrode GCE-Ru-AuNPs was finally washed with water to remove the excess of AuNPs and it was used to acetaminophen detection by cyclic voltammetry. To find the optimum analysis conditions of the modified electrode, studies were conducted to understand; which were: the number of cyclic voltammograms to produce the film, dip-coating time in AuNPs, pH, scan rate and repeatability. The Ru-AuNPs aggregates were analyzed by UV-Vis spectroscopy (UV-Vis), Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR), nuclear magnetic resonance of phosphorus ( 31P{1H} NMR), cyclic voltammetry (CV); scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) and transmission electron microscopy with energy dispersive spectroscopy (TEM-EDS). The X-ray structure of [RuCl(dppb)(5,5′-Me-bipy)(4-vpy)](PF6) was determinate.
- Ferreira, Vanessa F.,Do Prado, Cássio R.A.,Rodrigues, Carolina M.,Otubo, Larissa,Batista, Alzir A.,Da Cruz, José W.,Ellena, Javier,Dinelli, Luís R.,Bogado, André L.
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- Hydrohalogenation of N-acetyl(aroyl)-1,4-benzoquinone monoimines
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New N-acetyl-1,4-benzoquinone monoimines alkyl-substituted in the quinoid ring were synthesized. The hydrohalogenation of N-acetyl(aroyl)-1,4-benzoquinone monoimines proceeds exclusively in keeping with the 1,4-addition. The hydrochlorination occurs along the ionic mechanism, in the hydrobromination grows the role of the radical mechanism.
- Avdeenko,Konovalova,Ludchenko,Ledeneva,Vakulenko
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experimental part
p. 214 - 229
(2011/05/05)
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- Spectrophotometric Determination of Aspirin by Transacetylation of 4-Aminophenol
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Aspirin transacetylates 4-aminophenol, yielding acetaminophen (N-acetyl-4-aminophenol), which can be determined by its oxidation to an orange-yellow product either by iodylbenzene in acetone when the absorbance is measured at 430 nm or by photometric titration with 2-iodylbenzoate in acetone-water medium at 444 nm.Salicylic acid, salicylamide, oxyphenbutazone, caffeine, and sodium hydrogen carbonate do not interfere.Drug mixtures of acetaminophen and aspirin have been analyzed by determining acetaminophen alone directly with iodyl reagents and then determining acetaminophen plus aspirin after 4-aminophenol reaction; aspirin is found b y difference
- Verma, Krishna K.,Jain, Archana
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p. 821 - 824
(2007/10/02)
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- Hydrolysis of the Model Carcinogen N-(Pivaloyloxy)-4-methoxyacetanilide: Involvement of N-Acetyl-p-benzoquinone Imine
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Results of kinetic, 1H NMR, and HPLC studies show that N-(pivaloyloxy)-4-methoxyacetanilide (1a), a model for suspected carcinogenic metabolites of phenacetin (10), decomposes predominately into N-acetyl-p-benzoquinone imine (3) in aqueous solution.The only other product isolated from the decomposition of 1a is 4-methoxyacetanilide (7), which is produced in moderate yield at pH > 6.0.The available evidence indicates that both of these materials are produced by a nitrenium ion mechanism.In aqueous solutions containing KCl at pH 1H NMR results indicate that the intermediate is a carbinolamine (8).At pH > 6.0, the decomposition of 3 becomes very complicated.At high concentrations, 3 decomposes by a non-first order path into a material which appears to be oligomeric.At sufficiently low concentrations (ca. 2.5 x 10-6 M), the decomposition of 3 returns to a first-order process.Under these conditions, the major products of the reaction are 6 and acetaminophen (4).The measured standard reduction potential for 3 of 0.978 +/- 0.001 V indicates that it is a much stronger oxidizing agent than either p-benzoquinone or p-benzoquinone monoimine.However, at this time it is not possible to determine the identity of the species responsible for the reduction of 3 into 4 in aqueous solution.
- Novak, Michael,Pelecanou, Maria,Pollack, Lee
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p. 112 - 120
(2007/10/02)
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- Spectrophotometric and Titrimetric Determination of Carboxylic Acid Anhydrides
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Two redox methods are described for the determination of carboxylic acid anhydrides involving reaction with either an excess of 4-aminophenol or a measured but excessive amount of sulfanilamide and photometric titration of N-acyl-4-aminophenol with 2-iodylbenzoate by measuring the absorbance of orange-red product at 444 nm or the residual amount of sulfanilamide is determined by titration with chloramine-T in the presence of acidified potassium bromide using methyl red as visual indicator.Mixtures of certain anhydrides have also been analyzed by the 2-iodylbenzoate method.The methods are rapid, precise, and accurate.No correlation is needed if carboxylic and mineral acids are also present.Carboxylic acid chlorides also react quantitatively.
- Verma, Krishna K.,Tyagi, Pramila
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p. 2157 - 2160
(2007/10/02)
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- Voltammetry of Acetamidophen and Its Metabolites
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As background support for a study of acetaminophen metabolism by modern electroanalytical and liquid chromatographic techniques, the voltammetric characteristics are reported for acetaminophen and representatives of its known classes of metabolites.Excellent agreement is found between cyclic voltammograms of millimolar solutions and hydrodynamic voltammograms derived from nanogram quantities studied by chromatographically assisted hydrodynamic voltammetry.This electrochemical information is expected to find application in the qualitative and quantitative determination of acetaminophen metabolites in samples of physiological origin, ultimately revealing new details about the mechanism of acetaminophen toxicity.This work provides a model which can be employed for the study of numerous toxic aromatic amines and phenols.
- Miner, David J.,Rice, John R.,Riggin, Ralph M.,Kissinger, Peter T.
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p. 2258 - 2263
(2007/10/02)
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- N-Hydroxyacetaminophen: A Postulated Toxic Metabolite of Acetaminophen
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The decomposition of N-hydroxyacetaminophen has been shown to occur via an initial first-order dehydration step to N-acetyl-p-benzoquinone imine with a rate constant at pH 7.6 of 8.66*10-3 min-1 and a half-life of 80 min.This is followed by a complex reaction between the quinone imine and the N-hydroxy compound to ultimately yield p-nitrosophenol and acetaminophen.The glucuronide and sulfate conjugates of N-hydroxyacetaminophen have been observed as urinary metabolites of N-hydroxyacetaminophen.No N-hydroxylated metabolites were found among the metabolites of acetaminophen.These results have been interpreted to show that N-hydroxyacetaminophen is not a metabolite of acetaminophen.It is proposed that the hepatotoxicity and nephrotoxicity of acetaminophen are mediated by a direct oxidation of acetaminophen to the toxic reactive intermediate N-acetyl-p-benzoquinone imine by the cytochrome P450 dependent mixed-function oxidase system.
- Calder, Ian C.,Hart, Sandra J.,Healey, Kevin,Ham, Kathryn N.
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p. 988 - 993
(2007/10/02)
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