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Charcoal blockade is a useful approach to block gastrointestinal (GI) absorption of orally inhaled drug products (OIDPs) and therefore can be used effectively to determine drug absorption exclusively via the pulmonary route. Charcoal blockade efficiency (CBE) should be measured to show whether adequate blockade of GI exposure is achieved in bioequivalence (BE) study. The purpose of this study is to employ a model method to calculate the CBE for a pilot pharmacokinetic (PK) BE study of inhaled ipratropium bromide. This model method, based on a convolution integral, is built in-house using MATLAB package. The results demonstrated a full blockade of GI absorption of ipratropium bromide for both test and reference drug products. This study has shown that the model method may provide a useful approach for validation of charcoal blockade method used in PK BE study for OIDPs. The ability to use modeling may simplify human PK studies in general, and is particularly valuable when for ethical, technical or regulatory reasons administration of an orally swallowed form of the drug is not possible.

The aim of this study was to evaluate the pharmacokinetic bioequivalence of a generic budesonide nasal spray and a branded product in healthy Chinese subjects under fasting condition. A single-center, single-dose, randomized, open-label, crossover study was conducted in 32 healthy Chinese subjects under fasting condition. The subjects were administered 256 μg of generic budesonide nasal spray (test drug) or branded budesonide nasal spray (RHINOCORT AQUA, reference drug), respectively. For each period, the subjects were administered with 64 μg of budesonide per spray and 2 sprays for each nostril followed by a washout period of 7 days. Plasma concentration of budesonide was determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic (PK) parameters were calculated, and the bioequivalence was compared using the noncompartment model with the Phoenix WinNonlin 7.0 program. Results show that the 90% confidence intervals of the test/reference ratios of maximum concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity for the budesonide concentration were 84.8% to 102.7%, 84.6% to 94.4%, and 85.4% to 95.2%, respectively, all fall within the bioequivalent range of 80% to 125%. The test and reference budesonide nasal sprays were PK bioequivalents in healthy Chinese subjects with comparable PK parameters. No serious adverse events were reported, and the 2 products have a good and similar safety profile.

The importance of the "gut-liver axis" in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut-liver axis of various liver diseases, reflecting their health benefits in preventing/alleviating liver diseases. Moreover, some plant-based foods with potential gut-liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases.

Since rutting is a major distress in flexible pavements at intermediate and high temperatures, rutting models with concise expressions and satisfying accuracy can have considerable contributions to...

Albedo is an important indicator of the radiation reflectance of pavement surface and commonly measured using the field albedometer. In this study, factors affecting the field measurement of albedo including solar radiation intensity, incident angle and surrounding conditions were investigated. A new albedometer for laboratory testing of albedo and internal temperature at different depths in compacted asphalt mixture/Portland cement concrete (PCC) slabs was developed to overcome the negative effects of field measurements. Laboratory measurements of albedo were performed on three types of asphalt mixture (e.g. AC-13, SMA-13 and OGFC-13) and PCC with different surface textures using the developed albedometer. Three types of coating materials were prepared by mixing base material of transparent epoxy glue and the filler of Nano-TiO2, Micro-TiO2 and Nano-ZnO, respectively. The albedo and internal temperature of asphalt mixtures with coating materials were also measured and compared to those without coating materials. Results show that the developed laboratory albedometer can synchronously measure the accurate albedo and internal temperature of pavement materials. The albedo of three types of asphalt mixtures have a range of 5.46%–6.11%, while the albedo of PCC with different surface textures ranges from 22.8% to 26.4%. The gradation of asphalt mixture has little impact on the albedo. Rougher PCC surface reflect less solar radiation and produce a higher internal temperature. The filler of Micro-TiO2 in pavement coating has the better reflectance than Nano-TiO2 and Nano-ZnO.

In this study, four different emulsifiers were used to prepare asphalt emulsions. The effects of emulsifiers on emulsion stability were investigated using the storage stability test, laser particle size analyzer (LPSA), and differential scanning calorimetry (DSC). Furthermore, aggregate (0.15–0.3 mm) was mixed with asphalt emulsions to obtain emulsified asphalt mortar. The Brookfield rotational viscometer (BRV) was employed to determine the mortar viscosity and equilibration time. According to the laboratory results, the storage stability of asphalt emulsions were in agreement with the corresponding particle size and specific surface area. There was a linear relationship between the square of particle size and storage stability. In addition, the QA-emulsifier-prepared asphalt emulsion yielded the smallest particle size and greatest specific surface area. This indicated the QA asphalt emulsion had the highest storage stability, which was followed by AA, XA, and IM asphalt emulsion, respectively. The DSC results showed that the enthalpy change displayed a linear relationship with the equilibration time. It was also demonstrated that the XA asphalt emulsion had the highest thermal stability, which was followed by AA, IM, and QA asphalt emulsion, respectively. This implied that there was no consistent ranking between storage stability and thermal stability. Finally, the AA asphalt emulsion was selected to prepare microsurfacing mixtures. The performance tests results indicated that aggregate gradation, aggregate temperature, additional water content, cement content and sand equivalent affected the mixing time and demulsification time dramatically. The wet-track abrasion test (WTAT) results demonstrated that mixtures with higher asphalt emulsion content and sand equivalent tended to have a higher early strength and a lower moisture susceptibility.

HMA’s rutting characteristics and friction properties play vital roles in defining pavement structural functions and driving safety. This paper developed a novel vertically loaded wheel tester which can uniquely evaluate the rutting potential and friction resistance of eight multi-layer specimens with one experimental set-up. In this study, the rutting and friction resistance with loading cycles for four types of two-layer structures with different mixture combinations were experimentally determined. According to the results, the structures made with the AC-20 mixture as the bottom layer had significantly lower rutting depths; this infers the bottom layer properties have a more pronounced impact on the rutting resistance of the two-layer structure. For the friction resistance, the property of the top layer is more relevant the structure’s friction resistance, so use of the SMA-13 mixture in the top layer is favorable. The developed test method was validated with the simulation results using the Pavement ME.

The micro-cracking behavior of asphalt mixtures in the indirect tensile test (IDT) was studied by the discrete element modeling in this paper. A user-defined discrete element model was constructed and verified by the laboratory test results. The material mechanical behavior, the micro-cracking mode, the crack initiation and propagation, and the energy consumption during the IDT of asphalt mixtures were investigated. Firstly, the mechanical behavior of asphalt mixtures during the IDT was studied. The simulation results indicate that the bearing capacity of the sample is controlled by the micro-crack development. According to this feature, the mechanical behavior of asphalt mixtures during the IDT was divided into five stages. Secondly, the micro-cracking mode during the IDT was analyzed. The results show that the majority of micro-cracks are caused by normal tensile forces. And the crack initiation and propagation in asphalt mixture mainly happen between aggregates and asphalt mastic and in asphalt mastic. Thirdly, the crack initiation and propagation during the IDT were investigated. The simulation results show that the micro-cracks appear first at the top and bottom of the sample before peak load due to the local compression by the loading platens. And at the softening stage, the micro-cracks propagate rapidly, which causes apparent macro-cracks in the middle of the sample. Finally, the energy consumption during the IDT was explored. The results indicate that at a temperature of −10 °C the majority of energy is consumed by crack initiation and propagation during the IDT.

The formulation and device collectively constitute an inhalation drug product. Development of inhaled drugs must consider the compatibility between formulation and device in order to achieve the intended pharmaceutical performance and usability of the product to improve patient compliance with treatment instruction. From the points of formulation, device and patient use, this article summarizes the inhalation drugs, including pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), and nebulizer that are currently available in the US and UK markets. It also discusses the practical considerations for the development of inhalers and provides an update on the corresponding regulations of the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency).

As bituminous pavement is under the shady, humid or polluted environments, the bitumen undergoes the microbial degradation by different microorganisms to cause the aging. To understand the microbial aging of bitumen degraded by multiple microorganisms, the typical bacillus licheniformis (BL), bacillus subtilis (BS) and pseudomonas aeruginosa (PA) were selected to compound three microbial consortia in different proportions, and cultured in three culture mediums. A more suitable culture medium for the three microbial consortia is selected. The changes in microscopic morphology, components, molecular weight distributions, functional groups and micromechanical properties of aged bitumen were discussed. Results indicate that the peptone content change of culture medium obviously affects the propagation of microbial consortia. The prepared culture medium II meets the propagation requirements of the three microorganisms, improving their degradation ability. Additionally, the microbial consortia preferentially degrade bituminous light components as their nutrient sources, and show weak degradation ability to macromolecular components, producing potholes with layer structures on bituminous surface. Moreover, the smaller molecules are decreased, but the macromolecules are increased in aged bitumen. The molecular weight distribution of aged bitumen is narrowed. BS, BL and PA in the microbial consortium of S2 show better synergistic effect to efficiently degrade bitumen than those of S1 and S3. Finally, the carbonyl and sulfoxide contents are not changed obviously, but the methylene content is decreased to reflect the aging results of bitumen. The maximum adhesive force of aged bitumen is lowered to cause the decrease in adhesion work, reflecting the decrease in bituminous viscidity. The elastic modulus of bitumen shows an increasing trend as the aging duration is prolonged. The elastic modulus of aged bitumen by the microbial consortium of S2 is higher than those by S1 and S3. This study provides an insight into the microbial aging mechanism of bitumen by multiple microorganisms.

Permanent deformation is a long-term irrecoverable depression accumulated in the wheel path when the flexible pavement is subjected to heavy loads at high temperature, which can be simulated using the vertically loaded wheel test (VLWT) in the laboratory. The objective of this study is to develop a new approach to analyze the vertically loaded wheel test results based on the elastic-viscoelastic correspondence principle. The energy-based pseudo variables are proposed to perform rutting evaluation of asphalt mixtures in the VLWT. Four types of styrene-butadienestyrene modified asphalt mixtures were prepared to conduct the undamaged compressive dynamic modulus test at different temperatures. Then the master curves of dynamic modulus for these mixtures were converted to get the relaxation modulus. The innovative VLWT for four types of two-layer structure with different asphalt mixture combinations were performed to investigate the rutting development. After that, a new mechanical-empirical rutting prediction model was introduced to predict the rutting development for each layer in the two-layer structure. The energy-based pseudo variables including pseudo strain, pseudo strain rate and dissipated pseudo strain energy (DPSE) were introduced to correlate with the rutting resistance. The results show that the developed mechanical-empirical rutting prediction model is proficient in capturing the rutting development of a two-layer structure of asphalt mixtures measured by a vertically loaded wheel tester. The rutting contributions of the top and bottom layers can be separated using this model. Compared with the total strain, the pseudo strain which removes the viscoelastic effect, is more accurate to evaluate the permanent deformation in a cyclic loading condition. The DPSE increases with the increase of loading cycles and rut depth. Two typical stages with an inflection point can be observed from the test results which indicate that the faster to reach the inflection point, the better rutting performance will be achieved.

To further understand engineering properties of grouted macadam composite materials (GMCM) used as a surfacing layer in pavement, the mechanical properties and durability characteristics of GMCM were evaluated, and the relevant strength mechanisms were investigated at the micro level. Results indicate that GMCM has better high-temperature stability, fatigue performance and moisture stability than that of conventional asphalt mix, while it shows an acceptable decrease in low-temperature crack resistance due to the relative brittleness of hardened cement paste. The hardened cement paste also generates a spatial network crystalline lattice in asphalt mix skeleton to form a three-dimensional integral coagulation-crystalloid structure. This facilitates the asphalt mix skeleton and hardened cement paste to bear loads in unison and increase durability of the GMCM. Further, the fibre-like hydrated products of fresh cement slurry on the bitumen film surface increase the interfacial strength between bitumen and har...

The micro-mechanical response of asphalt mixtures was studied using the discrete element method. The discrete element sample of stone mastic asphalt was generated first and the vehicle load was applied to the sample. A user-written program was coded with the FISH language in PFC3D to extract the contact forces within the sample and the displacements of the particles. Then, the contact forces within the whole sample, in asphalt mastic, in coarse aggregates and between asphalt mastic and coarse aggregates were investigated. Finally, the movement of the particles in the sample was analyzed. The sample was divided into 15 areas and a figure was drawn to show how the balls move in each area according to the displacements of the balls in each area. The displacements of asphalt mastic balls and coarse aggregates were also analyzed. The experimental results explain how the asphalt mixture bears vehicle load and the potential reasons why the rutting forms from a micro-mechanical view.

This article describes regulatory approaches for approval of “generic” orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the “original” product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as “generic” and “reference” drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.

This paper discusses the anti-freezing capability of pavement mixtures, based on mix mass change in water and scattering loss in alternate freeze-thaw processes. The mechanism of asphalt mixture mass change and strength reduction is also analyzed. Test results show that the optimal bitumen content is 6-6.5% as determined by mass change in water before and after the freeze thaw test, compared with that of 6.5% as determined by mass scattering loss in alternate freeze-thaw processes. From test results, 6.3% is regarded as optimal bitumen content adapted to lower temperature regions; the optimal bitumen content is very close to asphalt content used in Qing-Hai Tibet highway.

The Zhaotong native copper deposit in Yunnan, Southwest China, is associated with the upper Middle Permian Emeishan flood basalts and is mainly hosted in the upper part of the Emeishan volcanic succession. Native copper mainly appears as disseminations in basaltic tuffs, and vesicular and brecciated tops of subaerial lava flows. Sheets of native copper up to 30 x 10 x 0.2 cm have also been found along fractures within the volcanic breccias. The native copper is associated with bitumen, zeolite, quartz, and calcite, typical of a low-temperature (100-150°C) hydrothermal alteration assemblage. The ore grades vary from ~0.1 to 20 wt% Cu. Copper was likely a result of organicinorganic interactions under conditions of the paucity of reduced S.

The LC–MS characteristics of budesonide and a series of structurally related corticosteroids were reviewed to commence the construction of a library of chromatographic and mass spectral information to aid identification of budesonide degradation products during formulation stabilization investigations. The LC–ESI + –MS technique employing a Hypersil ® C18 column with a mobile phase of ethanol-acetonitrile-formic acid (pH 3.8; 0.14 mM) (2:30:68, v/v/v) was then used to characterize 23 corticosteroids. Based on their structures, the corticosteroids were classified into three groups: (I) 4-pregnene-3-one steroids; (II) 1,4-pregnadien-3-one steroids with no fluorine substituents; and (III) 1,4-pregnadiene-3-one steroids with fluorine substituents. Chromatographic (retention time and UV absorbance) and mass spectral properties were correlated with the known chemical structures of these corticosteroids. Base peak and mass spectral fragmentation patterns were related to steroid structural characteristics.

The official (European) pharmacopeial assay for budesonide was found to be non-specific and non-stability-indicating when used to qualify several batches of pharmaceutical grade drug substance from different sources. In contrast, the most widely cited HPLC method in the literature was found to be specific and stability-indicating with respect to drug substance stored in the dry state. However, that method failed the pharmacopeia's assay system suitability requirements because of peak tailing. Moreover, it was unable to detect or resolve two major degradation products which resulted from drug storage in non-aqueous solution. A new stability-indicating HPLC method described here overcomes these problems. This method used a Hypersil C18 column with a mobile phase consisting of ethanol-acetonitrile phosphate buffer (pH 3.4; 25.6 mM) (2:30:68, v/v/v), a flow rate of 1.5 ml/min and UV detection at 240 nm. The purity of budesonide EP and its impurity profile (related substances) were tested using the new assay method, and the results compared to those from the two other methods described above. Solid-state and solution stressed stability samples were used to evaluate all methods. Using the novel method, the epimers of budesonide. their related impurities and degradation products were separated successfully. Validation studies demonstrated that the novel method possessed a linear UV response, good system precision and accuracy, high sensitivity and specificity for budesonide. The novel method will be used for future studies of budesonide's degradation kinetics.

The naturally occurring polyphenol compound resveratrol (RES) has been receiving wide attention because of its variety of health benefits and favourable biological activities. Previous studies have shown that RES could induce intestinal chloride secretion in mouse jejunum and stimulate cAMP-dependent Cl- secretion in T84, primary cultured murine nasal septal and human sinonasal epithelial cells, but the precise molecular target is not clear. We therefore tested the hypothesis that RES may stimulate the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Using cell-based fluorescent assays, transepithelial short-circuit current measurements and excised inside-out patch-clamp analysis; we found that RES dose-dependently potentiate CFTR Cl- channel activities, which was reversed by CFTR inhibitors CFTR(inh)-172 and GlyH101. Transepithelial Cl- secretion by CFTR-expressing FRT cells was stimulated by RES with half maximal concentration -80 microM. Intracellular cAMP content was not elevated by RES in FRT cells. Excised inside-out patch-clamp analysis indicated that RES significantly increased the chloride currents of CFTR. In ex vivo studies, RES stimulated the transmucosal chloride current of rat colon by short-circuit current assay. These data suggested that CFTR is a molecular target of RES. Our findings add a new molecular target to RES, and RES may represent a novel class of therapeutic lead compounds in treating CFTR-related diseases including CF and habitual constipation.

This is a brief report of a new occurrence of eocrinoids from the Early Cambrian Wulongqing Formation in Yunnan, China. The eocrinoids from the Guanshan fauna are among the earliest known eocrinoids. Different from many other Early and Middle Cambrian eocrinoids, the Guanshan eocrinoids are char-acterized by the absence of sutural pores and epispires, the long and spiral brachioles, the extremely long stalk, and the ratio of the length of the stalk versus that of the calyx. The discovery of the eocri-noids from the Guanshan fauna not only provides new information to the investigation of the early evolution of this animal group, but also shed new light on the occurrence and migration of early eocrinoids.

In this study, to design a satisfactory asphalt mixture skeleton for semi-flexible pavement (SFP), the effects of aggregate gradation on grouting results of porous asphalt mixture were analyzed based on the test results of 22 aggregate gradations. Moreover, the mix design method of asphalt mixture skeleton was also discussed. Results indicated that the grouting effects of asphalt mixture skeleton were affected by its internal void interconnectivity, including the morphological characteristics, structure, and size of pores, instead of the initial void volume (VV). The grouting effects of asphalt mixture skeleton were influenced by the fine aggregate at the specific particle size levels. An increase in the mixing proportion of coarse aggregates could improve the grouting effects. A valid mix design approach was developed to prepare the asphalt mixture skeleton of SFP. Finally, engineering properties of the grouted mixture specimens were validated. It was concluded that the aggregation gradation design was a very important aspect in effecting the grouting results of an asphalt mixture skeleton. Furthermore, the aggregate gradation should be selected to facilitate the cement slurry to permeate in full thickness of the asphalt mixture skeleton layer. This could be used to direct the design of asphalt mixture skeleton toward lessening field failures on the SFP.

The discrete element method is now increasingly used in the micro-mechanical analysis of asphalt mixtures. The digital image-based method is usually used to prepare the two-dimensional (2D) discrete element sample. However, this method is costly and time-consuming. In this study, a series of algorithms were developed to generate the 2D discrete element sample of asphalt mixtures based on the probability analysis. Firstly, the shapes and sizes of the 2D aggregates cut from three-dimensional 3D aggregates were analyzed and their probabilities were computed. Based on this, an algorithm was proposed to generate the 2D aggregates. Secondly, a method was developed to calculate the number of 2D aggregates in the 2D asphalt mixture sample. Lastly, the algorithms for generating the 2D discrete element sample were summarized and discussed. With these algorithms, the 2D discrete element sample of asphalt mixtures can be generated directly and rapidly.