A new method for evaluating the bitterness of medicines by semi-continuous measurement of adsorption using a taste sensor

We describe a new method for the evaluation of the bitterness of medicines by semi-continuous measurement of adsorption using a multichannel taste sensor or 'electric tongue'. The bitterness of 10 basic medicines was evaluated by both the taste sensor and in human gustatory sensation tests with 11 volunteers. The sensor part of the taste sensor consists of eight electrodes made of lipid/polymer membranes. Three variables were obtained from the taste sensor data: sensor output (S), the change of membrane potential caused by adsorption, corresponding to aftertaste (C), and the ratio C/S. These variables were used to predict an estimated bitterness score in multiple regression analysis. Semi-continuous measurement of C (every 30 s up to 150 s) was adopted as an additional explanatory variable, and the attenuation rate of C was defined as C'. These data were also subjected to multiple regression analysis. The correlation coefficient (r) estimated for the bitterness score predicted by the taste sensor, using C' for channel 2 and C/S for channel 4, and the score obtained by human gustatory sensation, was 0.824. This value was greater than that obtained using C/S for both channels 2 and 4 (0.734). The method described in the present study seems to offer good predictability for the evaluation of bitterness.     

Masking mechanisms of bitter taste of drugs studied with ion selective electrodes

The masking mechanisms of the bitter taste of propantheline bromide (PB) and oxyphenonium (OB) bromide by native and modified cyclodextrins, saccharides, surfactants, organic acids, nonionic and anionic polymers, and other compounds were investigated with ion selective electrodes. The intensity of the bitter taste for a mixed solution of cyclodextrin with PB or OB was quantitatively explained from the observed electromotive force with the following assumptions: the complex and the masking agent do not have any tastes and the bitter taste is independent of other tastes. Sodium dodecyl sulfate reduced the bitter taste remarkably, and this reduction was also explicable on the basis of the same mechanism. Sodium taurodeoxycholate enhanced the bitter taste, because of its strong bitterness, although it formed 1 : 1 complexes with PB and OB. The masking mechanism of saccharides was ascribed to overcoming the weak bitterness of the drug by the strong sweetness. Lambda-carrageenan suppressed the bitter taste remarkably. This suppression was ascribed to the binding of PB and OB to lambda-carrageenan, the effect of the solution viscosity on the bitter taste, and the covering of the bitter taste receptor by lambda-carrageenan. It was suggested that the moderate masking by other polymers was attributable to the effect of the solution viscosity or the receptor covering. Native and modified beta-cyclodextrins, sodium dodecyl sulfate, lambda-carrageenan, Tween 20, and sodium carboxymethyl cellulose are good masking agents for the bitter tastes of PB and OB. The drug ion selective electrode is a useful tool for understanding of the masking mechanism of the bitter taste, screening of masking agents, and estimation of appropriate concentrations of the masking agents.     

High-content screening of drug-induced cardiotoxicity using quantitative single cell imaging cytometry on microfluidic device

Drug-induced cardiotoxicity or cytotoxicity followed by cell death in cardiac muscle is one of the major concerns in drug development. Herein, we report a high-content quantitative multicolor single cell imaging tool for automatic screening of drug-induced cardiotoxicity in an intact cell. A tunable multicolor imaging system coupled with a miniaturized sample platform was destined to elucidate drug-induced cardiotoxicity via simultaneous quantitative monitoring of intracellular sodium ion concentration, potassium ion channel permeability and apoptosis/necrosis in H9c2(2-1) cell line. Cells were treated with cisapride (a human ether-à-go-go-related gene (hERG) channel blocker), digoxin (Na(+)/K(+)-pump blocker), camptothecin (anticancer agent) and a newly synthesized anti-cancer drug candidate (SH-03). Decrease in potassium channel permeability in cisapride-treated cells indicated that it can also inhibit the trafficking of the hERG channel. Digoxin treatment resulted in an increase of intracellular [Na(+)]. However, it did not affect potassium channel permeability. Camptothecin and SH-03 did not show any cytotoxic effect at normal use (≤300 nM and 10 μM, respectively). This result clearly indicates the potential of SH-03 as a new anticancer drug candidate. The developed method was also used to correlate the cell death pathway with alterations in intracellular [Na(+)]. The developed protocol can directly depict and quantitate targeted cellular responses, subsequently enabling an automated, easy to operate tool that is applicable to drug-induced cytotoxicity monitoring with special reference to next generation drug discovery screening. This multicolor imaging based system has great potential as a complementary system to the conventional patch clamp technique and flow cytometric measurement for the screening of drug cardiotoxicity.     

The bitterness intensity of clarithromycin evaluated by a taste sensor

The purpose of this study was to evaluate the ability of a quantitative prediction method using a taste sensor to determine the bitterness of clarithromycin powder suspensions of various concentrations and of a commercial clarithromycin dry syrup product (Clarith dry syrup, Taisho Pharmaceutical Co., Ltd., Tokyo) containing aminoalkyl methacrylate polymer as a taste-masker. The bitterness of the clarithromycin dry syrup product dissolved in various beverages was also evaluated in gustatory sensation tests and using the taste sensor. In the sensor measurements, three variables were used to predict bitterness in single and multiple regression analysis: relative sensor output (R), the change of membrane potential caused by adsorption (CPA), and CPA/R ratio. The CPA values for channel 3 of the sensor predicted well the bitterness of clarithromycin powder suspensions and their filtered solutions. For Clarith dry syrup, the sensor output was small, suggesting that aminoalkyl methacrylate polymer was successful in almost complete masking of the bitter taste of the dry syrup product. When the bitterness intensities of mixtures of 1 g of Clarith dry syrup with 25 ml of water, coffee, tea, green tea, cocoa, milk, and a sports drink were examined, a good correlation was obtained between the results from human taste tests and the predicted values calculated on the basis of multiple regression analysis using CPA data from channel 4, and the CPA/R ratio from channel 3 of the taste sensor (r(2)=0.963, p<0.005). Co-administration of 1 g of Clarith dry syrup with an acidic sports drink was found to be the most bitter using either method.     

An SKP and EIS investigation of amine adsorption on zinc oxide surfaces

A metal/oxide/polymer ‘interphase’ with mixed organic–inorganic nature insures the high stability and the strength of the adhesive joints in a variety of corrosive environments. To model the interaction of epoxy resin with a metal surface, the interaction of amines of different structure with oxidized zinc surfaces was studied by Scanning Kelvin Probe (SKP), FTIR microscopy in atmospheric conditions, and a.c. and d.c. electrochemical techniques in the aqueous electrolyte. It was shown that bidentate ligand‐ethylendiamine, forming stable chelate complexes reacts with zinc oxide with redeposition of the interphase. In air and water electrolyte, this ligand shifts the potential of Zn/ZnO electrode to the level of the oxide‐free zinc. The amines with low chelating property show low effect on the potential of Zn/ZnO. The SKP was used to measure the potential drop at epoxy resin/zinc interface. On this basis, SKP is proposed as a sensitive nondestructive technique to characterize in situ the interaction of the resin with the metal and the subsequent formation of the interphase in the metal–polymer joints. Copyright © 2010 John Wiley & Sons, Ltd.     

Solid-state ion selective electrode based on polypyrrole conducting polymer nanofilm as a new potentiometric sensor for Zn2+ ion

A pencil graphite electrode (PGE) electrodeposited by a polypyrrole conducting polymer doped with tartrazine (termed as PGE/PPy/Tar) was prepared and used as a zinc (II) solid-state ion-selective electrode. For the preparation of the zinc sensor electrode, electrodeposition of a polypyrrole nanofilm was carried out potentiostatically (E _app?=?0.75 V vs SCE) in a solution containing 0.010 M pyrrole and 0.001 M tartrazine trisodium salt. A pencil graphite and Pt wire were used as working and auxiliary electrodes, respectively. The introduced electrode in the current paper can be fabricated simply and was found to possess high selectivity, exhibited wide working concentration range, sufficiently rapid response, potential stability, and very good sensitivity to Zn (II) ion. The sensor electrode showed a linear Nernstian response over the range of 1.0?×?10^?5 to 1.0?×?10^?1 M with a slope of 28.23 mV per decade change in zinc ion concentration. A detection limit of 8.0?×?10^?6 M was obtained. The optimum pH working of the electrode was found to be 5.0.     

纳米铜修饰三维锌网电极的制备及锌离子电池负极的电化学性能

设计构建了纳米铜修饰的三维锌网电极(Nano Cu@3D Zn Mesh, 简称3D Cu-Zn电极), 并将其作为锌沉积的宿主材料用作锌离子电池的负极, 获得了稳定的、 具有长循环寿命的锌负极材料. 3D Cu-Zn电极的三维(3D)锌网骨架和表面均匀分布的3D树枝状纳米铜可以降低局部电流密度, 并为锌的沉积提供结构支撑和容纳空间. 锌网表面具有的较强锌结合能力的铜和后续原位形成的铜锌合金, 可以有效降低锌形核的过电势, 并作为均匀分布的形核位点引导锌的均匀成核和沉积. 这种3D Cu-Zn电极宿主材料表现出较低的形核过电势和界面阻抗, 并在对称电池中表现出优异的循环稳定性, 在0.5 mA/cm²的电流密度下可以稳定循环超过1100 h. 3D Cu-Zn电极与MnO₂组装的全电池表现出更小的极化、 良好的倍率性能和循环性能.     

Metal‐imprinted microsphere prepared by surface template polymerization and its application to chromatography

A metal ion‐imprinted microsphere was prepared by surface molecular template polymerization. Trimethylolpropane trimethacrylate (TRIM), zinc ions, 1,12‐dodecanediol‐O, O′‐diphenyl phosphonic acid (DDDPA) were used as a crosslinking agent, an imprint molecule, and a functional host molecule. The Zn(II)‐imprinted microspheres, which are spherically well‐defined particles, were prepared by using water‐in‐oil‐in‐water (W/O/W) multiple emulsions. The combination of TRIM and DDDPA serves to align the recognition sites resulting in better template sites produced on the polymer surface. We firstly conducted diagnostic zinc‐ and copper‐ion adsorption tests with the Zn(II)‐imprinted and unimprinted microspheres in order to make an assessment on the effectiveness of the molecular imprinting technique. Further, the metal‐imprinted microspheres were applied to the column operation. The separation and recovery of metals were carried out by an adsorption column packed with the Zn(II)‐imprinted microspheres. This performance was compared to that of commercial chelating resins that possess similar phosphoric functional groups. The Zn(II)‐imprinted polymer shows an extremely high selectivity to the imprinted zinc ions compared to that of the commercial chelating resin. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 689–696, 2000     

Step by Step Induced Growth of Zinc-Metal Interface on Graphdiyne for Aqueous Zinc-Ion Batteries

Rechargeable aqueous zinc ion batteries (AZIBs) promise high energy density, low redox potential, low cost and safety; however, their cycle performances are seriously insufficient to restrict the progress in this field. We propose a new concept of atomic electrode formed on the graphdiyne (GDY). This new idea electrode was synthesized by selectively, uniformly, and stably anchoring Zn atoms on GDY at the beginning of plating. The Zn atoms are induced to grow into larger size Zn clusters, which continue to grow into nanoflat. Finally, a new heterojunction interface is formed on GDY without any Zn dendrites and side reactions, even at high current densities. Such stepwise induction of growth greatly suppresses the formation of Zn dendrites, resulting in high electroplating/stripping reversibility and lifespan of AZIBs.     

Fabrication and photoluminescent properties of ZnO/mesoporous silica composites templated by a chelating surfactant

A novel anionic surfactant-templated synthesis of ZnO/mesoporous silica nanocomposites has been carried out by using N-hexadecylethylenediamine triacetate (HED3A), a triprotic surfactant, as the structure-directing agent. The chelating template can capture zinc ions in solution and then direct the mesophase formation, enabling an amount of zinc oxide to be embedded in the porous silica matrix during calcination. With variation of the molar ratio of Zn(2+) to HED3A in the template, a series of composites with different doping amounts were obtained after the removal of organic components. The variation of the zinc ion concentration in the initial template solution induces an evolution of the silica mesophase, presumably due to the change in electronegativity of the HED3A headgroup caused by the chelating effect. Spectroscopic studies show a strong host-guest interaction between the silica pore walls and ultrafine ZnO nanoparticles. The photoluminescence properties of the resulting composites exhibit a size-dependent light emission and quantum-confinement effect of ZnO, accompanied by an infrequent violet emission originating from the ZnO-SiO(2) interface.     

电位控制ZnO/表面活性剂复合多层膜在固/液界面上的自组装

通过控制固/液界面电极电位的方式, 控制表面活性剂和金属离子在电极表面的自组装, 制备出了高度取向的ZnO/表面活性剂复合多层膜. 对无机层形态和结构进行了分析, 并采用X射线反射率和X射线漫散射研究了电极电位控制下ZnO/表面活性剂复合多层膜在固/液界面的自组装生长. 结果表明, 在一定电位下, 只有当表面活性剂浓度低于其饱和吸附浓度时, 采用阶跃电位沉积方式才能明显改变复合薄膜的周期厚度; 恒电位沉积方式控制电极电位时, 随着沉积电位的提高, 多层膜层状结构由一组层状相变为多组层状相, 同时层状结构的取向变差. 实验研究结果验证了电化学自组装过程是由金属离子的还原速度和表面活性剂的吸附速度二者共同控制完成的.     

Ion exchange chromatography of aluminum using 3-carboxy-2-naphthylamine-N,N-diacetic acid as a fluorescent post-column chelating reagent

Ion exchange chromatography of aluminum ion using 3-carboxy-2-naphthylamine-N,N-diacetic acid (CNDA) as a fluorescent post-column chelating reagent was studied. The solution containing ammonium chloride and hydrochloric acid was used for the eluent, and acetate buffer solution containing CNDA was used for the post column chelating reagent. The peak of aluminum was separated from that of calcium, magnesium and zinc, and the chromatogram was not affected by copper(II) and iron(III). The calibration curve gave linear plots with a range of 0.0027-0.54 ppm aluminum, the regression coefficient of correlation (r2) was 1.000, and the detection limit (S/N = 3) was 0.3 ppb, indicating that the method could determine aluminum with high sensitivity. It was demonstrated that CNDA is a useful metallofluorescent reagent for aluminum. This method has been successfully applied to the determination of aluminum in some tea drinks.     

锌电极在氢氧化钾溶液中阳极惰化时的表面相变的研究

本文试图进一步从动力学方面证明恒电位下的锌电极在KOH溶液中阳极惰化时,阳极溶解电流随时间而缓慢下降是由于“表面相变”所引起。用恒电位法测取了锌电极在不同浓度的KOH溶液中电流对时间的曲线。实验结果与推导的动力学方程式相符,表明在恒电位惰化条件下,锌电极表面上最初形成的[Zn(OH)_2]_(ad)在OH~-参预下徐缓地转变为较不易溶的[ZnO]_(ad),因而导致阳极溶解电流的下降。这一表面相变过程可表示如下:     

The Application of Nafion Metal Catalyst Free Carbon Nanotube Modified Gold Electrode: Voltammetric Zinc Detection in Serum

Metal catalyst free carbon nanotube (MCFCNT) whiskers were first used as an electrode modification material on a gold electrode surface for zinc voltammetric measurements. A composite film of Nafion and MCFCNT whiskers was applied to a gold electrode surface to form a mechanically stable sensor. The sensor was then used for zinc detection in both acetate buffer solution and extracted bovine serum solution. A limit of detection of 53 nM was achieved for a 120 s deposition time. The zinc in bovine serum was extracted via a double extraction procedure using dithizone in chloroform as a zinc chelating ligand. The modified electrode was found to be both reliable and sensitive for zinc measurements in both matrices.     

Extraction of Copper(II) and Zinc(II) from Chloride Media with Mixed Extractants

Extraction of copper(II) and zinc(II) from acidic chloride solutions with mixtures of two extractants: a basic or solvating one and a chelating extractant was discussed. Processes for recovery and separation of Cu(II) from Zn(II) were proposed, which consist of the following steps: extraction from chloride media with the formation of metal chlorocomplex ion pair or solvate, scrubbing of chloride ions with an aqueous solution of appropriate pH with simultaneous transfer of the metal ion to the chelate, traditional stripping with sulphuric acid and conditioning of the basic extractant. Both effective recovery and separation of metal ions with simultaneous change of the system from the chloride to the sulphate state can be achieved. A bifunctional reagent, such as alkyl derivative of 8-hydroxyquinoline, can be also used instead of the extractant mixture.     

Investigation of materials for making a carbon-support zinc-selective electrode

The usefulness of zinc orthophosphate and zinc mercuric thiocyanate to make a carbon-support electrode responsive to zinc was investigated. The best results were obtained with zinc orthophosphate, which produced a Nernstian response to zinc in the concentration range from 10(-5) to 10(-2)M. The electrode response was lowered by the formation of acidic oxides on the surface of the electrode. Different ways of minimizing this problem are discussed. Interference effects from copper(II) (K(pot)(Zn.Cu) = 1.0), cadmium (K(pot)(Zn.Cd) = 8.9) and lead (K(pot)(Zn.Pb) = 10) were observed.     

Electrochemical synthesis of Zn-Al layered double hydroxide (LDH) films

A new electrodeposition condition to produce Zn-Al LDH films was developed using nitrate solutions containing Zn (2+) and Al (3+) ions. Deposition was achieved by reducing nitrate ions to generate hydroxide ions on the working electrode. This elevates the local pH on the working electrode, resulting in precipitation of Zn-Al LDH films. The effect of deposition potential, pH of the plating solution, and the Zn (2+) to Al (3+) ratio in the plating solution on the purity and crystallinity of the LDH films deposited was systematically studied using X-ray diffraction and energy dispersive spectroscopy (EDS). The optimum deposition potential to deposit pure and well-ordered Zn-Al LDH films was E = -1.65V versus a Ag/AgCl in 4 M KCl reference electrode at room temperature using a solution containing 12.5 mM Zn(NO 3) 2.6H 2O and 7.5 mM Al(NO 3) 3.9H 2O with pH adjusted to 3.8. The resulting film contained 39 atomic %Al (3+) ions replacing Zn (2+) ions, leading to a composition of Zn 0.61Al 0.39(OH) 2(NO 3) 0.39. xH 2O. Increasing or decreasing the aluminum concentration in the plating solution resulted in the formation of aluminum- or zinc-containing impurities, respectively, instead of varying aluminum content incorporated into the LDH phase. Choosing an optimum deposition potential was important to obtain LDH as a pure phase in the film. When the potential more negative than the optimum potential is used, zinc metal or zinc hydroxide was deposited as a side product, whereas making the potential less negative than the optimum potential resulted in the formation of zinc oxide as the major phase. The pH condition of the plating solution was also critical, as increasing pH destabilizes the formation of the LDH phase while decreasing pH promoted deposition of other impurities.     

Kinetics of the Zn(II)/Zn(Hg) electrode reactions in DMSO solutions of halide ions

The electrode reaction Zn(II)/Zn(Hg) in complex chloride, bromide, and iodide solutions with DMSO as solvent and ammonium perchlorate as supporting electrolyte has been studied at the equilibrium potential by the faradaic impedance method and a square-wave method. Furthermore, double-layer data have been determined by electrocapillary measurements. The results indicate that the zinc chloride and bromide complexes do not contribute noticeably to the exchange current density, while in the iodide system both the solvated zinc ion and the first complex take part in the charge transfer. From the dissimilar results valid for water and DMSO solutions the conclusion is made that probably ligand bridging at the amalgam by the halide ions is operative in water solutions, whereas in DMSO the larger solvent molecules adsorbed can form a steric hindrance to ligand bridging by chloride or bromide ions.     

浙江省宁波、海宁部分地区幼儿头发和全血中的微量元素相关性研究

测定了浙江省宁波、海宁部分地区223例3-4岁健康幼儿同一个体头发和全血铅和锌含量,并研究两类样本两种微量元素的相关性。发现除血锌男女性别间含量差异不明显外,发中的锌、铅,全血中的铅均有显著的性别差异;无论是头发或是全血,男性或女性铅和锌均呈负相关且大多数有显著性;发铅和血铅男性和女性均呈显著正相关,而发锌与血锌女性也呈显著相关。本文还求出发铅与血铅、发锌与血锌含量间的一元线性回归方程。     

Reaction of metal-binding ligands with the zinc proteome: zinc sensors and N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine

The commonly used Zn(2+) sensors 6-methoxy-8-p-toluenesulfonamidoquinoline (TSQ) and Zinquin have been shown to image zinc proteins as a result of the formation of sensor-zinc-protein ternary adducts not Zn(TSQ)(2) or Zn(Zinquin)(2) complexes. The powerful, cell-permeant chelating agent N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) is also used in conjunction with these and other Zn(2+) sensors to validate that the observed fluorescence enhancement seen with the sensors depends on intracellular interaction with Zn(2+). We demonstrated that the kinetics of the reaction of TPEN with cells pretreated with TSQ or Zinquin was not consistent with its reaction with Zn(TSQ)(2) or Zn(Zinquin)(2). Instead, TPEN and other chelating agents extract between 25 and 35% of the Zn(2+) bound to the proteome, including zinc(2+) from zinc metallothionein, and thereby quench some, but not all, of the sensor-zinc-protein fluorescence. Another mechanism in which TPEN exchanges with TSQ or Zinquin to form TPEN-zinc-protein adducts found support in the reactions of TPEN with Zinquin-zinc-alcohol dehydrogenase. TPEN also removed one of the two Zn(2+) ions per monomer from zinc-alcohol dehydrogenase and zinc-alkaline phosphatase, consistent with its ligand substitution reactivity with the zinc proteome.