Sulfonic Functionalized Polydopamine Coatings with pH-Independent Surface Charge for Optimizing Capillary Electrophoretic Separations.

Enhancing the pH-independence and controlling the magnitude of electroosmotic flow (EOF) are critical for highly efficient and reproducible capillary electrophoresis (CE) separations. Herein, we present a novel capillary modification method utilizing sulfonated periodate-induced polydopamine (SPD) coating to achieve pH-independent and highly reproducible cathodic EOF in CE. The SPD-coated capillaries were obtained through post-sulfonation treatment of periodate-induced PDA (PDA-SP) coatings adhered on the capillary inner surface. The successful immobilization of the SPD coating and the substantial grafting of sulfonic acid groups were confirmed by a series of characterization techniques. The excellent capability of PDA-SP@capillary in masking silanol groups and maintaining a highly robust EOF mobility was verified. Additionally, the parameters of sulfonation affecting the EOF mobilities were thoroughly examined. The obtained optimum SPD-coated column offered the anticipated highly pH-independent and high-strength cathodic EOF, which is essential for enhancing the CE separation performance and improving analysis efficiency. Consequently, the developed SPD-coated capillaries enabled successful high-efficiency separation of aromatic acids and nucleosides and rapid cyclodextrin-based chiral analysis of racemic drugs. Moreover, the SPD-coated columns exhibited a long lifetime and demonstrated good intra-day, inter-day, and column-to-column repeatability.

Bicarbonate directly modulates activity of chemosensitive neurons in the retrotrapezoid nucleus.

KEY POINTS: Changes in CO2 result in corresponding changes in both H+ and HCO3- and despite evidence that HCO3- can function as an independent signalling molecule, there is little evidence suggesting HCO3- contributes to respiratory chemoreception. We show that HCO3- directly activates chemosensitive retrotrapezoid nucleus (RTN) neurons. Identifying all relevant signalling molecules is essential for understanding how chemoreceptors function, and because HCO3- and H+ are buffered by separate cellular mechanisms, having the ability to sense both modalities adds additional information regarding changes in CO2 that are not necessarily reflected by pH alone. HCO3- may be particularly important for regulating activity of RTN chemoreceptors during sustained intracellular acidifications when TASK-2 channels, which appear to be the sole intracellular pH sensor, are minimally active. ABSTRACT: Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue CO2 /H+ . The retrotrapezoid nucleus (RTN) is an important site of respiratory chemoreception. Mechanisms underlying RTN chemoreception involve H+ -mediated activation of chemosensitive neurons and CO2 /H+ -evoked ATP-purinergic signalling by local astrocytes, which activates chemosensitive neurons directly and indirectly by maintaining vascular tone when CO2 /H+ levels are high. Although changes in CO2 result in corresponding changes in both H+ and HCO3- and despite evidence that HCO3- can function as an independent signalling molecule, there is little evidence suggesting HCO3- contributes to respiratory chemoreception. Therefore, the goal of this study was to determine whether HCO3- regulates activity of chemosensitive RTN neurons independent of pH. Cell-attached recordings were used to monitor activity of chemosensitive RTN neurons in brainstem slices (300 µm thick) isolated from rat pups (postnatal days 7-11) during exposure to low or high concentrations of HCO3- . In a subset of experiments, we also included 2',7'-bis(2carboxyethyl)-5-(and 6)-carboxyfluorescein (BCECF) in the internal solution to measure pHi under each experimental condition. We found that HCO3- activates chemosensitive RTN neurons by mechanisms independent of intracellular or extracellular pH, glutamate, GABA, glycine or purinergic signalling, soluble adenylyl cyclase activity, nitric oxide or KCNQ channels. These results establish HCO3- as a novel independent modulator of chemoreceptor activity, and because the levels of HCO3- along with H+ are buffered by independent cellular mechanisms, these results suggest HCO3- chemoreception adds additional information regarding changes in CO2 that are not necessarily reflected by pH.

Investigation on the pH-independent photoluminescence emission from carbon dots impregnated on polymer matrix.

Highly luminescent, polymer nanocomposite films based on poly(vinyl alcohol) (PVA), and monodispersed carbon dots (C-dots) derived from multiwalled carbon nanotubes (MWCNTs), as coatings on substrates as well as free standing ones are obtained via solution-based techniques. The synthesized films exhibit pH-independent photoluminescence (PL) emission, which is an advantageous property compared with the pH-dependent photoluminescence intensity variations, generally observed for the C-dots dispersed in aqueous solution. The synthesized C-dots and the nanocomposite films are characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infra-red spectroscopy (FTIR), ultraviolet (UV) - visible spectroscopy and photoluminescence spectroscopy (PL) techniques. The TEM image provides clear evidence for the formation of C-dots of almost uniform shape and average size of about 8 nm, homogeneously dispersed in aqueous medium. The strong anchoring of C-dots within the polymer matrix can be confirmed from the XRD results. The FTIR spectral studies conclusively establish the presence of oxygen functional groups on the surfaces of the C-dots. The photoluminescence (PL) emission spectra of the nanocomposite films are broad, covering most part of the visible region. The PL spectra do not show any luminescence intensity variations, when the pH of the medium is changed from 1 to 11. The pH-independent luminescence, shown by these films offers ample scope for using them as coatings for designing diagnostic and imaging tools in bio medical applications. The non-toxic nature of these nanocomposite films has been established on the basis of cytotoxicity studies.

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools.

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a 'One factor at a time (OFAT)' approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.

Extended release of flurbiprofen from tromethamine-buffered HPMC hydrophilic matrix tablets.

The pH-dependent solubility of a drug can lead to pH-dependent drug release from hydrophilic matrix tablets. Adding buffer salts to the formulation to attempt to mitigate this can impair matrix hydration and negatively impact drug release. An evaluation of the buffering of hydrophilic matrix tablets containing a pH-dependent solubility weak acid drug (flurbiprofen), identified as possessing a deleterious effect on hydroxypropyl methylcellulose (HPMC) solubility, swelling and gelation, with respect to drug dissolution and the characteristics of the hydrophilic matrix gel layer in the presence of tromethamine as a buffer was undertaken. The inclusion of tromethamine as an alkalizing agent afforded pH-independent flurbiprofen release from matrices based on both HPMC 2910 (E series) and 2208 (K series), while concomitantly decreasing the apparent critical effect on dissolution mediated by this drug with respect to the early pseudo-gel layer formation and functionality. Drug release profiles were unaffected by matrix pH-changes resulting from loss of tromethamine over time, suggesting that HPMC inhibited precipitation of drug from supersaturated solution in the hydrated matrix. We propose that facilitation of diffusion-based release of potentially deleterious drugs in hydrophilic matrices may be achieved through judicious selection of a buffering species.

Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug.

The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH 6.8 and pH 1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24 h in acidic media (pH 1.2). The release profile in acidic media was similar to the alkaline media (pH 6.8) with a similarity factor (f2) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile.

A pH-independent instantaneous release of flurbiprofen: a study of the preparation of complexes, their characterization and in vitro/in vivo evaluation.

In this study, furbiprofen/hydroxypropyl-ß-cyclodextrin (HPßCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPßCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPßCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPßCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPßCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPßCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.

Influence of pH Modulation on Dynamic Behavior of Gel Layer and Release of Weakly Basic Drug from HPMC/Wax Matrices, Controlled by Acidic Modifiers Evaluated by Multivariate Data Analysis.

The solubility of weakly basic drugs in passage through gastrointestinal tract leads to their pH-dependent release from extended release formulations and to lower drug absorption and bioavailability. The aim of this study was to modulate the micro-environmental pH of hypromellose/montanglycol wax matrices and to observe its influence on the release of weakly basic drug verapamil hydrochloride (VH) with a pH-dependent solubility with respect to gel layer formation and its dynamics. For this study, malic and succinic acids differing in their solubility and pKa were selected as pH modifiers. The dissolution studies were performed by the method of changing pH. Within the same conditions, pH, thickness, and penetration force of the gel layer were measured as well. From the PCA sub-model, it is evident that a higher acid concentration ensured lower gel pH and conditions for higher drug solubility, thus creating larger gel layer with smaller rigidity, resulting in higher VH release during the dissolution test. Incorporation of stronger and more soluble malic acid (100 mg/tablet) created the most acidic and the thickest gel layer through which a total of 74% of VH was released. Despite having lower strength and solubility, matrices containing succinic acid (100 mg/tablet) released a comparable 71% of VH in a manner close to zero-order kinetics. The thinner and less rigid gel layers of the succinic acid matrices allowed an even slightly faster VH release at pH 6.8 than from matrices containing malic acid. Thus acid solubility is more parametrically significant than acid pKa for drug release at pH 6.8.

Evaluation of Matrix Tablets Based on Eudragit®E100/Carbopol®971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol.

The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.

Exquisite visualization of mitophagy and monitoring the increase of lysosomal micro-viscosity in mitophagy with an unusual pH-independent lysosomal rotor.

BACKGROUND: Mitophagy plays indispensable roles in maintaining intracellular homeostasis in most eukaryotic cells by selectively eliminating superfluous components or damaged organelles. Thus, the co-operation of mitochondrial probes and lysosomal probes was presented to directly monitor mitophagy in dual colors. Nowadays, most of the lysosomal probes are composed of groups sensitive to pH, such as morpholine, amine and other weak bases. However, the pH in lysosomes would fluctuate in the process of mitophagy, leading to the optical interference. Thus, it is crucial to develop a pH-insensitive probe to overcome this tough problem to achieve exquisite visualization of mitophagy. RESULTS: In this study, we rationally prepared a pH-independent lysosome probe to reduce the optical interference in mitophagy, and thus the process of mitophagy could be directly monitored in dual color through cooperation between IVDI and MTR, depending on Förster resonance energy transfer mechanism. IVDI shows remarkable fluorescence enhancement toward the increase of viscosity, and the fluorescence barely changes when pH varies. Due to the sensitivity to viscosity, the probe can visualize micro-viscosity alterations in lysosomes without washing procedures, and it showed better imaging properties than LTR. Thanks to the inertia of IVDI to pH, IVDI can exquisitely monitor mitophagy with MTR by FRET mechanism despite the changes of lysosomal pH in mitophagy, and the reduced fluorescence intensity ratio of green and red channels can indicate the occurrence of mitophagy. Based on the properties mentioned above, the real-time increase of micro-viscosity in lysosomes during mitophagy was exquisitely monitored through employing IVDI. SIGNIFICANCE AND NOVELTY: Compared with the lysosomal fluorescent probes sensitive to pH, the pH-inert probe could reduce the influence of pH variation during mitophagy to achieve exquisite visualization of mitophagy in real-time. Besides, the probe could monitor the increase of lysosomal micro-viscosity in mitophagy. So, the probe possesses tremendous potential in the visualization of dynamic changes related to lysosomes in various physiological processes.

Signal-sustained imaging of mitophagy with an Enzyme-Activatable Metabolic Lipid-Labeling Probe.

Imaging of mitophagy is of significance as aberrant mitophagy is engaged in multiple diseases. Mitophagy has been imaged with synthetic or biotic pH sensors by reporting pH acidification en route delivery into lysosomes. To circumvent uncertainty of acidity-dependent signals, we herein report an enzyme-activatable probe covalently attached on mitochondrial inner membrane (ECAM) for signal-persist mitophagy imaging. ECAM is operated via ΔΨm-driven accumulation of Mito-proGreen in mitochondria and covalent linking of the trapped probe with azidophospholipids metabolically incorporated into the mitochondrial inner membrane. Upon mitophagy, ECAM is delivered into lysosomes and hydrolyzed by LNPEP/leucyl aminopeptidase, yielding turn-on green fluorescence that is immune to lysosomal acidity changes and stably retained in fixed cells. With ECAM, phorbol-12-myristate-13-acetate (PMA) was identified as a highly potent inducer of mitophagy. Overcoming signal susceptibility of pH probes and liability of ΔΨm probes to dissipation from stressed mitochondria, ECAM offers an attractive tool to study mitophagy and mitophagy-inducing therapeutic agents.

Always positive covalent organic nanosheet enabling pH-independent adsorption and removal of Cr(â ¥).

Rapid and highly effective removal of hexavalent chromium (Cr(Ⅵ)) is extremely vital to water resources restoration and environmental protection. To overcome the pH limitation faced by most ionic absorbents, an always positive covalent organic nanosheet (CON) material was prepared and its Cr(VI) adsorption and removal capability was investigated in detail. As-prepared EB-TFB CON (TFB = 1,3,5-benzaldehyde, EB = ethidium bromide) shows strong electropositivity in the tested pH range of 1 ∼ 10, display a pH-independent Cr(VI) removal ability, and work well for Cr(VI) pollution treatment with good anti-interference capability and reusability in a wide pH range covering almost all Cr(VI)-contaminated real water samples, thus eliminating the requirement for pH adjustment. Moreover, the nanosheet structure, which is obtained by a facile ultrasonic-assisted self-exfoliation, endows EB-TFB CON with fully exposed active sites and shortened mass transfer channels, and the Cr(VI) adsorption equilibrium can be reached within 15 min with a high adsorption capacity of 280.57 mg·g-1. The proposed Cr(VI) removal mechanism, which is attributed to the synergetic contributions of electrostatic adsorption, ion exchange and chemical reduction, is demonstrated by experiments and theoretical calculations. This work not only provides a general Cr(VI) absorbent without pH limitation, but also presents a paradigm to prepare ionic CONs with relatively constant surface charges.

Rational Design of pH-Independent and High-Fidelity Near-Infrared Tunable Fluorescent Probes for Tracking Leucine Aminopeptidase In Vivo.

Accurate detection of target analytes and generation of high-fidelity fluorescence signals are particularly critical in life sciences and clinical diagnostics. However, the majority of current NIR-I fluorescent probes are vulnerable to pH effects resulting in signal distortion. In this work, a series of fluorescence-tunable and pH-independent probes are reported by combining optically tunable groups of unsymmetric Si-rhodamines and introducing the methoxy instead of the spiro ring on the benzene ring at position 9. To validate the concept, the leucine aminopeptidase response site was introduced into Si-2,6OMe-NH2 with the best optical properties to synthesize Si-LAP for monitoring the intrahepatic LAP in vivo. Therefore, the design approach may provide a new and practical strategy for designing innovative functional fluorescent probes and generating high-stability and high-fidelity fluorescent signals.

Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery.

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Measuring Intracellular H 2 O 2 in Intact Human Cells Using the Genetically Encoded Fluorescent Sensor HyPer7.

Depending on its local concentration, hydrogen peroxide (H2O2) can serve as a cellular signaling molecule but can also cause damage to biomolecules. The levels of H 2O2 are influenced by the activity of its generator sites, local antioxidative systems, and the metabolic state of the cell. To study and understand the role of H2O2 in cellular signaling, it is crucial to assess its dynamics with high spatiotemporal resolution. Measuring these subcellular H2O2 dynamics has been challenging. However, with the introduction of the super sensitive pH-independent genetically encoded fluorescent H2O2sensor HyPer7, many limitations of previous measurement approaches could be overcome. Here, we describe a method to measure local H2O2 dynamics in intact human cells, utilizing the HyPer7 sensor in combination with a microscopic multi-mode microplate reader. Graphical abstract: Overview of HyPer7 sensor function and measurement results.

Preparation of biochar-interpenetrated iron-alginate hydrogel as a pH-independent sorbent for removal of Cr(VI) and Pb(II).

Herein, a pH-independent interpenetrating polymeric networks (Fe-SA-C) were fabricated from graphitic biochar (BC) and iron-alginate hydrogel (Fe-SA) for removal of Cr(VI) and Pb(II) in aqueous solution. Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and scanning electron microscope (SEM) results demonstrated that graphitic BC interpenetration increased surface porosity and distorted surfaces of Fe-SA, which boosted availability of hydroxyl (-OH) group. Fe3+ as a cross-linking agent of the alginate endowed Fe-SA-C with positive surfaces (positive zeta potential) and excellent pH buffering capacity, while excessive Fe3+ was soldered on Fe-SA-C matrix as FeO(OH) and Fe2O3. Cr(VI) removal at pH of 3 by Fe-SA-C (20.3 mg g-1) were 30.3% and 410.6% greater than that by Fe-SA and BC, respectively. Fe-SA-C exhibited minor pH dependence over pH range of 2-7 towards Cr(VI) retention. Greater zeta potential of Fe-SA-C over Fe-SA conferred a better electrostatic attraction with Cr(VI). FTIR and XPS of spent sorbents confirmed the reduction accounted for 98.5% for Cr(VI) removal mainly due to participation of -OH. Cr(VI) reduction was further favored by conductive carbon matrix in Fe-SA-C, as evidenced by more negative Tafel corrosion potential. Reductively formed Cr(III) was subsequently complexed with carboxylic groups originating from oxidation of -OH. Thus, Cr(VI) removal invoked electrostatic attraction, reduction, and surface complexation mechanisms. Pb(II) removal with excellent pH independence was mainly ascribed to surface complexation and possible precipitation. Thus, the functionalized, conductive, and positively-charged Fe-SA-C extended its applicability for Cr(VI) and Pb(II) removal from aqueous solutions in a wide pH range. This research could expand the application of hydrogel materials for removal of both cationic and anionic heavy metals in solutions over an extended pH range.

Microenvironmental pH-modified Amisulpride-Labrasol matrix tablets: development, optimization and in vivo pharmacokinetic study.

Amisulpride (AMS) is atypical antipsychotic with a weak basic nature (pKa 9.37), which results in low solubility in the high pH of the intestine. It is also recognized as a substrate of P-glycoprotein efflux pump. Both factors lead to its low oral bioavailability (48%). The daily dose of AMS is between 200 and 1200 mg to be taken in divided doses which compromise patient compliance. Therefore, controlled release formulation of AMS is of clinical significance. AMS was formulated into matrix tablets containing Labrasol, P-glycoprotein efflux inhibitor, and a penetration enhancer, using direct compression technique. The tablets were prepared according to 21·41 factorial design using two polymers, namely, HPMC and Carbopol 934 at four concentrations (20%, 30%, 40%, 50%). Percentage AMS released after 2 h (Q2hr%) and 8 h (Q8hr%) were chosen as dependent variables. Two acidic pH modifiers (fumaric acid and tartaric acid) at two levels (15% and 30%) were incorporated in the tablet according to 22 factorial design. All formulae with acidic pH modifier had similarity factor (f2) ≥ 50 proving the pH independent release of AMS. The pharmacokinetic study in rabbits revealed 30% enhancement of the oral absorption AMS imparted by the pH-modified matrix tablet containing Labrasol. Graphical abstract.

Repurposing of antiparasitic niclosamide to inhibit respiratory syncytial virus (RSV) replication.

Despite being an important health problem, there are only supportive care treatments for respiratory syncytial virus (RSV) infection. Thus, discovery of specific therapeutic drugs for RSV is still needed. Recently, an antiparasitic drug niclosamide has shown a broad-spectrum antiviral activity. Here, our in vitro model was used to study the antiviral effect of niclosamide on RSV and its related mechanism. Niclosamide inhibited RSV with time and dose-dependent manner. Pretreatment with submicromolar concentration of niclosamide for 6 h presented the highest anti-RSV activity of 94 % (50 % effective concentration; EC50 of 0.022 µM). Niclosamide efficiently blocked infection of laboratory strains and clinical isolates of both RSV-A and RSV-B in a bronchial epithelial cell line. Although a disruption of the mechanistic target of rapamycin complex 1 (mTORC1) pathway by niclosamide was previously hypothesized as a mechanism against pH-independent viruses like RSV, using a chemical mTORC1 inhibitor, temsirolimus, and a chemical mTORC1 agonist, MHY1485 (MHY), we show here that the mechanism of RSV inhibition by niclosamide was mTORC1 independent. Indeed, our data indicated that niclosamide hindered RSV infection via proapoptotic activity by a reduction of AKT prosurvival protein, activation of cleaved caspase-3 and PARP (poly ADP-ribose polymerase), and an early apoptosis induction.

Oil-Membrane Protection of Electrochemical Sensors for Fouling- and pH-Insensitive Detection of Lipophilic Analytes.

To take full advantage of the reagent- and label-free sensing capabilities of electrochemical sensors, a frequent and remaining challenge is interference and degradation of the sensors due to uncontrolled pH or salinity in the sample solution or foulants from the sample solution. Here, we present an oil-membrane sensor protection technique that allows for the permeation of hydrophobic (lipophilic) analytes into a sealed sensor compartment containing ideal salinity and pH conditions while simultaneously blocking common hydrophilic interferents (proteins, acids, bases, etc.) In this paper, we validate the oil-membrane sensor protection technique by demonstrating continuous cortisol detection via electrochemical aptamer-based (EAB) sensors. The encapsulated EAB cortisol sensor exhibits a 5 min concentration-on rise time and maintains a measurement signal of at least 7 h even in the extreme condition of an acidic solution of pH 3.

Application of solid waste of ductile cast iron industry for treatment of wastewater contaminated by reactive blue dye via appropriate nano-porous magnesium oxide.

The solid waste of ductile iron industry, which contains at least 88.0% magnesium oxide, is one of the toxic materials, leading to land contamination. On the other hand, the removal of reactive dyes from wastewaters is difficult required effective adsorbent like nano-porous MgO. The novelty of present investigation is based on nano-porous magnesium oxide production by precipitation from the solid waste to treat the wastewaters contaminated by reactive dye which is abundantly used in the textile industry. In order to improve the adsorptive properties of extracted MgO powder, the combinations of surfactants, containing cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS) and polyoxyethylene octyl phenyl ether (TX100) were applied based on the mixture design algorithm in the precipitation. The effects of processing factors such as surfactant composition, powder calcination temperature, surfactant dose and pH were evaluated on the removal efficiency. The results revolved that the combination of SDS and TX100, 1:1, plays an effective role in the production of particles with the appropriate average pore size, 16 nm. The adsorbent prepared in the optimum condition indicated a significant affinity for the removal of reactive dye which shows relatively pH-independent efficiency in the range of 3-9. The applied producer for fabrication of adsorbent eventually overcomes the pH-dependent problem for the toxic dye uptake, leading to produce the adsorbent with maximal adsorption capacity of 1000 mg g-1.