Development and validation of an LC-MS/MS method for simultaneous determination of EVT201 and its five metabolites in human plasma: Application to a clinical study in Chinese healthy subjects.

EVT201 is a partial GABAA receptor agonist, which inhibits nervous system to treat insomnia. EVT201 can form a variety of metabolites in vivo including Ro46-1927, Ro18-5528, Ro40-9970, Ro66-9196 and Ro66-5448. This study developed a simple method to realize the simultaneous determination of EVT201 and its five metabolites by HPLC-MS/MS with an electrospray ion source (ESI). The deuterium substitute of EVT201 was chosen as the internal standard and the multiple reaction monitoring (MRM) was used for the quantification. The separation of the six compounds was accomplished with an ACE Excel 3 AQ column (50 × 2.1 mm, 3 µm, ACE). The process of protein precipitating-transferring-nitrogen blowing-reconstituting was adopted for the sample pretreatment. This method was successfully validated according to the FDA guidance. Calibration curves were linear over the concentration range of 0.100-100 ng/mL for EVT201, 0.0300-30.0 ng/mL for Ro46-1927, 0.0600-6.00 ng/mL for Ro18-5528, 0.0200-4.00 ng/mL for Ro40-9970, 0.100-20.0 ng/mL for Ro66-9196 and 0.100-20.0 ng/mL for Ro66-5448. The intra-run and inter-run precisions and accuracies were all within 14.5%. This fully validated method was successfully applied to a clinical pharmacokinetic study of EVT201 and its five metabolites in Chinese healthy subjects after the single (2.5 mg and 5 mg, N = 12) and multiple dose (2.5 mg, N = 13) administration of EVT201 capsules. The test results of 2.5 mg dose group showed that for EVT201, Ro46-1927, Ro18-5528, Ro40-9970, Ro66-9196 and Ro66-5448, the Cmax values (ng/mL) were 39.2 ± 9.2, 10.3 ± 1.4, 0.218 ± 0.044, 0.128 ± 0.051, 7.01 ± 1.51, 8.73 ± 3.69, respectively; the AUC0-t values (h·ng/mL) were 231 ± 79, 143 ± 72, 10.9 ± 2.1, 1.84 ± 0.78, 55.9 ± 18.7, 135 ± 40 respectively. For EVT201, Ro46-1927, Ro66-5528, Ro66-9196 and Ro40-5448, the results of Cmax and AUC0-t proved that the five compounds showed linear pharmacokinetic profile over the dose ranges of 2.5 mg to 5 mg. Meanwhile, it is the first report to evaluate the pharmacokinetic characteristics of Ro40-9970, Ro66-9196 and Ro66-5448 in human plasma. It provided meaningful parameters for the safety and tolerability evaluation of EVT201 capsules in human.

Simultaneous determination of maltol and maltol glucuronide in human plasma and urine by HPLC-MS/MS: Application in clinical study in patients with iron deficiency.

Ferric maltol has been used as an oral drug for iron deficiency. This study developed and fully validated the novel HPLC-MS/MS methods to determine maltol and maltol glucuronide simultaneously in plasma and urine. The protein precipitation was performed by addition of acetonitrile in the plasma samples. The dilution was performed for the urine samples to reach the suitable concentrations for injection. The multiple reaction monitoring (MRM) with an electrospray ionization (ESI) positive ion detection mode was used for the quantification. The maltol concentration linear ranges were 6.00-150 ng/mL and 0.100-10.0 µg/mL for the plasma and urine samples, respectively. The maltol glucuronide concentration linear ranges were 50.0-15000 ng/mL and 2.00-2000 µg/mL for the plasma and urine samples, respectively. These methods were applied to a single dose clinical study at a dose of 60 mg ferric maltol capsule in the patients with iron deficiency. The half-lives of maltol and maltol glucuronide were 0.90 ± 0.40 h and 1.02 ± 0.25 h in the iron deficiency patients, respectively. 39.52 ± 7.11 % maltol were excreted in urine in the form of maltol glucuronide.

Case Study on Prestressed CFRP Plates Applied for Strengthening Hollow-Section Beam Removed from an Old Bridge.

With the wide application of carbon fiber reinforced polymer (CFRP) plate, used for strengthening existed concrete structures, the prestressing technology of CFRP plate is becoming a hot topic, in order to sufficiently develop its high-strength peculiarity. In this paper, a full-scale hollow-section beam with length of 16 m taken from an old bridge which was in service for about 20 years was first examined for existed cracks and repaired by filling epoxy adhesive, and then the beam was strengthened with prestressed CFRP plates. The CFRP plates were tensioned and fixed with flat-plate anchorages at ends and bonded with adhesive on the bottom surface of the beam. The strengthened beam was experimentally studied using a four-point test to measure the concrete strain along the height of the mid-span section and the mid-span deflection. The finite element model of the strengthened beam was verified by the comparison of test results and used for an extending study of parametric analysis considering the effect of the length and amount of CFRP plates. Results indicated that with an increase in the length and amount of CFRP plates, the mid-span deflection of the beam decreases with the increased cracking resistance and bearing capacity, while the ultimate failure mode transfers from the under-reinforcement to the over-reinforcement.

Seismic performance analysis of shallow-buried large-scale three-box-section segment-connected pipeline structure under multiple actions.

To ensure the safety operation of inter-basin water transfer project, it is important to understand the seismic performance of shallow-buried large-scale segment-connected pipeline structure under earthquake and other multiple actions. In this paper, a 3D FE model is built in details for the seismic assessment of large-scale prestressed concrete inverted-siphon shallow-buried under riverbed, and a method is proposed to realize multiple interactions of the viscoelastic boundary elements to finite elements, the compressible fluid to structure and the sealed joints made of rubber belt between adjacent segments. The inverted-siphon is longitudinally composited by 58 segments in total length of 858.64 m, and transversally consisits of three rectanguler-section boxes with net dimension of each box of 6.5 m width and 6.6 m height. The main influencing factors are set as the thickness of overburden soil, the flow condition and the engineering geological condition. The time-history analysis is carried out on the 3D FE model under Elcentro seismic wave excitation. The numerical analyses figures out the main vibration modes and vibrational frequency of this inverted-siphon, reveals the regions of peak tensile stress appeared on the concrete surface and the risk sealed joints with extremum relative displacement. This provides a scientific reference to take specific prevention measures of anti-earthquake, based on a deep understanding to the seismic cracking of concrete and the tearing broken of sealed joints for this kind of segment-connected pipeline structure.

Bond Behavior of Steel Bars in Concrete Confined with Stirrups under Freeze-Thaw Cycles.

In order to evaluate the influence of freeze-thaw action on the durability of concrete structures, this paper presented an experimental study to investigate the effects of freezing-thawing cycles and concrete strength on the bond behavior between steel bars and concrete confined with stirrups. Through freeze-thaw cycles and center pullout tests, the failure mode of pullout specimen, concrete strength, mass loss, dynamic elastic modulus, and bond-slip curves were analyzed. At last, the bond-slip constitutive model was proposed for specimens with stirrup confinement under freeze-thaw action. Main test results indicate that the failure mode and shape of bond-slip curves are affected by stirrups. The bond strength hasa certain increase after 100 freeze-thaw cycles owing to the constraining force from stirrups, whereas the splitting tensile strength significantly declines. After 100 freeze-thaw cycles, the splitting tensile strength of C20 and C40 decreased by 40.8% and 46.5%, respectively. The formula was provided to calculate the bond strength of constrained concrete after freeze-thaw cycles, and the damage coefficient and other related parameters in the formula were suggested. The predicted bond-slip curves are close to the experimental results, which could provide reference for the related research of bond performance after freeze-thaw action.

Bond Behaviors of Steel Fiber in Mortar Affected by Inclination Angle and Fiber Spacing.

Considering the random orientation and distribution of steel fibers in concrete, the synergistic reinforcement of steel fibers on concrete is much complex than the bond of single fiber. It is meaningful to study the bond behavior of steel fiber during many actions. With the inclination angle of steel fiber to pullout direction and the fiber spacing as main factors, this paper carried out fifteen groups of pullout tests for hook-end steel fiber embedded in manufactured sand mortar. The inclination angle ranged from 0 to 60°, and the fiber spacing ranged from 3.5 mm to 21.2 mm. The characteristic pullout load-slip (PL-S) curve of steel fibers are given out after treating the original complete curves of each group test. The values of key points featured the debonding, peak and residual pullout loads and slips are determined from the characteristic PL-S curves. Based on a multi-index synthetical evaluation method, the nominal debonding strength, bond strength, residual bond strength and the debonding work, slipping work, and pullout work, as well as the debonding energy ratio, slipping energy ratio, and pullout energy ratio are analyzed. Results indicate that the bond performance represented by above indexes changes with the inclination angle and spacing of steel fibers. Except for the bond mechanism performing the same as aligned steel fibers by pullout test, the bond is dominated by the resistance of mortar to peeling off near pullout surface and scraping along pullout direction. When the inclination angle is over 15° or 30°, the bond performance is generally decreased, due to the peeling off of mortar on surface of transversal section with a certain depth. When the fiber spacing is over than 5 mm, the bond performance becomes worst due to the scraping out of mortar along with the slip of steel fibers.

Investigating the Mechanical Property and Enhanced Mechanism of Modified Pisha Sandstone Geopolymer via Ion Exchange Solidification.

The Yellow River has the highest sediment concentration in the world, and the Yellow River coarse sediment mainly comes from a particular kind of argillaceous sandstone, Pisha sandstone. This paper reports an investigation of the possibility of development of low-cost engineering materials using Pisha sandstone via ion exchange modification. The effect of modifiers with different concentration on the inhibition of volume expansion and the strength enhancement of modified Pisha sandstone were studied via ion exchange solidification. The effects of the concentration of ten types of modifier solutions and curing age were considered. The hydration of the mineral components, particle surface potential and reaction products were studied, respectively, by XRD, zeta potential, TG/DTG and SEM. Expansion volume and shear strength tests were conducted to assess the volume stability and mechanical property of modified Pisha sandstone. It showed that the expansion of Pisha sandstone was controlled and that the volume stability and shear strength were improved via ion exchange modification. The results of XRD, TG/DTG and SEM showed that the spacing of the crystal layers of the Pisha sandstone clay mineral and the mass lost had decreased significantly. When the concentration of the modifier was 0.05 mol/L, the volume reduced by 54.55% maximum and the shear strength reached the peak of 138 kPa.

Experimental Study on Chloride Ion Diffusion in Concrete Affected by Exposure Conditions.

The transport mechanism of chloride ions in concrete is relatively complicated since the erosion process is influenced by many factors. To investigate the effect of exposure conditions on the chloride ion diffusion property, three exposure conditions (long-term immersion in static sodium chloride solution, long-term immersion in circulating sodium chloride solution and dry-wet cycles in circulating sodium chloride solution) were considered in chloride ion diffusion experiments. Experimental results indicated that the chloride ion content at a certain depth increased with erosion age. The chloride ions in static sodium chloride solution transported more rapidly than those under dry-wet cycle conditions. Moreover, the chloride ion content of concrete under dry-wet cycles of the circulating sodium chloride solution was slightly higher than that under long-term immersion in the circulating solution. Based on Fick's second law, empirical equations for the chloride diffusion coefficient and chloride content at the surface of concrete were proposed by fitting experimental data, and the values of correlation coefficients of different exposure conditions were suggested. By comparison with the experiment results, it was verified that the calculation formula had better applicability. This method could be used to predict and analyze the chloride ion content under different exposure conditions.

Influence of Particle Morphology of Ground Fly Ash on the Fluidity and Strength of Cement Paste.

The grinding process has become widely used to improve the fineness and performance of fly ash. However, most studies focus on the particle size distribution of ground fly ash, while the particle morphology is also an important factor to affect the performance of cement paste. This article aims at three different kinds of ground fly ash from the ball mill and vertical mill, and the particle morphology is observed by scanning electron microscopy (SEM) to calculate the spherical destruction (the ratio of spherical particles broken into irregular particles in the grinding process of fly ash), which provides a quantification of the morphology change in the grinding process. The fluidity of cement paste and the strength of cement mortar are tested to study the relation of spherical destruction and fluidity and strength. The results show that the spherical destruction of ground fly ash in a ball mill is more than 80% and that in a vertical mill with a separation system is only 11.9%. Spherical destruction shows a significant relation with the fluidity. To different addition of ground fly ash, the fluidity of cement paste decreases with the increase of spherical destruction. To the strength of cement paste, particle size distribution and spherical destruction are both the key factors. Therefore, spherical destruction is an important measurement index to evaluate the grinding effect of the fly ash mill.

Development and validation of samples stabilization strategy and LC-MS/MS method for simultaneous determination of clevidipine and its primary metabolite in human plasma: Application to clinical pharmacokinetic study in Chinese healthy volunteers.

A feasible LC-MS/MS method with reliable stabilizers consisted of sodium fluoride, ascorbic acid and formic acid was developed and validated for the determination of clevidipine and its primary metabolite (H152/81) in human plasma. Sodium fluoride existing in the vacutainer tubes was used to inhibit esterase activity to protect the clevidipine from hydrolysis as soon as blood was collected. Ascorbic acid and formic acid were added to the separated plasma samples to avoid the oxidation and further hydrolysis of clevidipine and H152/81. The further sample preparation was accomplished through a single step liquid-liquid extraction (LLE) by ethyl acetate. The chromatography separation was carried out on an ACE Excel 3 µm SuperC18 (2.1 × 50 mm, id, ACE, United Kingdom) column with gradient elution using 10 mM ammonium acetate water solution and methanol as the mobile phase. Detection was performed in the negative ion electrospray ionization mode using multiple reaction monitoring (clevidipine: m/z 454.1 â†’ 234.0; clevidipine-d7: m/z 461.1 â†’ 240.1; H152/81: m/z 354.0 â†’ 208.0; H152/81-13CD3: m/z 358.0 â†’ 212.0). The method exhibited good linearity over the concentration ranges of 0.100 to 40.0 ng/mL for clevidipine and 5.00 to 400 ng/mL for H152/81. The intra- and inter-batch precision and accuracy of clevidipine and H152/81 were all within the acceptable criteria. The method was successfully applied to a pharmacokinetic study of clevidipine and H152/81 in healthy Chinese volunteers following 8 mg/h intravenous infusion of clevidipine butyrate injectable emulsion for 0.5 h. The results showed that clevidipine was rapidly eliminated with a short half-life time of 0.244 ± 0.125 h and a maximum concentration of 25.2 ± 7.09 ng/mL. H152/81 was detectable in the plasma samples up to 48.5 h with a half-life time of 10.7 ± 2.30 h and a maximum plasma concentration of 301 ± 38.1 ng/mL.

LC-APCI-MS/MS assay for quantitation of ethyl esters of eicosapentaenoic acid and docosahexaenoic acid in human plasma and its application in a pharmacokinetic study.

A simple and specific LC-MS/MS method was developed and validated for the determination of ethyl ester of eicosapentaenoic acid (EPAEE) and ethyl ester of docosahexaenoic acid (DHAEE). After deproteinized with acetonitrile, the plasma samples were separated on a C18 column using a gradient elution system consisted of methanol and 1.0 mM ammonium acetate in water. The detection used an atmospheric-pressure chemical ionization ion source in positive mode with multiple reaction monitoring for the quantitation of EPAEE and DHAEE. The acceptable linearity was achieved over the concentration ranges of 1.00~1000 ng/mL for EPAEE and 2.50~2500 ng/mL for DHAEE. The method was successfully applied to a pharmacokinetic study of EPAEE and DHAEE in healthy Chinese volunteers after the oral administration of 4 g omega-3-acid ethyl esters 90 soft capsule. The pharmacokinetic profiles of EPAEE and DHAEE were observed for the first time in Chinese volunteers, which reached a maximum concentration of 499 ± 243 ng/mL and 1596 ± 476 ng/mL for EPAEE and DHAEE, respectively. The areas under the plasma concentration-time curve were 1290 ± 765 ng/mL·h for EPAEE and 4369 ± 1680 ng/mL·h for DHAEE, respectively.

A simplified and reliable LC-tandem mass spectrometry method for determination of ulipristal acetate in human plasma and its application to a pharmacokinetic study in healthy Chinese volunteers.

In this study, a simplified, sensitive and reliable LC-tandem mass spectrometry method was established and validated for the quantification of ulipristal acetate (UPA) in human plasma and for the investigation of pharmacokinetic profile of UPA following a single oral administration of ella (UPA 30-mg tablet) in healthy Chinese volunteers. Plasma samples were analyzed after being processed by protein precipitation with methanol. Chromatographic separation was performed on a Kinetex EVO C18 column (2.1 × 50 mm, 2.6 µm) using gradient elution with a mobile phase composed of methanol and water containing 2 mm ammonium acetate and 0.3% formic acid at a flow rate of 0.3 mL/min. The chromatographic running time was 4.0 min per sample. The MS detection was performed via an LC system with the positive ion electrospray ionization interface in multiple reaction monitoring mode using the transition of m/z 476.2 → 134.1 for UPA and m/z 479.3 → 416.2 for UPA-d3 [internal standard (IS)], respectively. UPA and IS were monitored without severe interference from the biological matrices. The method was linear over the wide concentration range of 0.300-300 ng/mL. The intra- and inter-day precision and accuracy were well within the limits required for bioanalytical assays. The method was first used to describe the pharmacokinetic characteristic of UPA after a single oral administration of ella in healthy Chinese volunteers. Based on a between-study comparison, there were statistically significant differences (p < .05) between Chinese and Caucasian volunteers for the systemic exposure of UPA, suggesting that race seems to significantly impact the systemic exposure of UPA.

Two high-performance liquid chromatography-tandem mass spectrometry methods for determination of edaravone and taurine in human plasma: Application to drug-drug interaction and pharmacokinetic studies.

Two high-performance liquid chromatography-tandem mass spectrometry methods were developed and validated for the quantification of edaravone (method A) or taurine (method B) in human plasma. After protein precipitation, separations were achieved on an Ultimate XB-C8 (2.1 × 50 mm, 3.0 µm) column for edaravone and a ZORBAX SB-Aq column (2.1 × 100 mm, 3.5 µm) for taurine, respectively. The detection used electrospray ionization source via multiple reaction monitoring in positive-ion mode for edaravone and negative-ion mode for taurine, respectively. The lower limits of quantification were 10.0 ng/mL for edaravone and 3.00 µg/mL for taurine. The selectivity, accuracy, and precision of the methods were all within acceptable limits. Two methods were successfully applied to a drug-drug interaction study and a pharmacokinetic study of edaravone and taurine in healthy Chinese volunteers after intravenous infusion of single or compound injection. The results showed that co-administration of edaravone with taurine increased the Cmax and AUC0-24 of taurine in human plasma while taurine did not affect the systemic exposure of edaravone. Edaravone and taurine have the dose-dependent pharmacokinetic profiles in human.

Shrinkage and Mechanical Properties of Self-Compacting SFRC With Calcium-Sulfoaluminate Expansive Agent.

With the premise of ensuring workability on a fresh mixture, the volume stability of hardened self-compacting steel fiber reinforced concrete (SFRC) becomes an issue due to the content of cementitious materials increased with the volume fraction of steel fiber. By using the expansive agent to reduce the shrinkage deformation of self-compacting SFRC, the strength reduction of hardened self-compacting SFRC is another issue. To solve these issues, this paper performed an experimental investigation on the workability, shrinkage, and mechanical properties of self-compacting SFRC compared to the self-compacting concrete (SCC) with or without an expansive agent. The calcium-sulfoaluminate expansive agent with content optimized to be 10% mass of binders and the steel fiber with a varying volume fraction from 0.4% to 1.2% were selected as the main parameters. The mix proportion of self-compacting SFRC with expansive agent was designed by the direct absolute volume method, of which the steel fibers are considered to be the distributed coarse aggregates. Results showed that rational high filling and passing ability of fresh self-compacting SFRC was ensured by increasing the binder to coarse-aggregate ratio and the sand ratio in the mix proportions; the autogenous and drying shrinkages of hardened self-compacting SFRC reduced by 22.2% to 3.2% and by 18.5% to 7.3% compared to those of the SCC without expansive agent at a curing age of 180 d, although the expansion effect of expansive agent decreased with the increasing volume fraction of steel fiber; the mechanical properties, including the compressive strength, the splitting tensile strength, and the modulus of elasticity increased with the incorporation of an expansive agent and steel fibers, which met the design requirements.

Bond Properties of Steel Bar in Concrete under Water Environment.

The present study concerns the bond behavior of steel bar in concrete under a water environment. This topic was put forward because of the changes of concrete under a water environment and the importance of reliable anchorage of steel bar for reinforced concrete structures. Thirty bond specimens with deformed steel bars were immersed in water and experimentally studied by pull-out tests. The soaking time from 28 day to 360 day and the cubic compressive strength of concrete with 20 N/mm2 and 40 N/mm2 were considered as the main parameters. The results indicate that the moisture content, compressive strength, and splitting tensile strength of concrete are affected by the water environment; the splitting tensile strength varies almost linearly with the compressive strength of concrete; and the descent portion of the bond-slip curve dropped slowly owing to the confinement of stirrups. On the basis of the test data, the formulas for the prediction of bond strength, residual strength, and the corresponding slips with different soaking time are proposed. Finally, the constitutive relation of bond-slip with two portions in the water environment is established with good agreement with the experimental bond-slip curves.

Complete Stress-Strain Curves of Self-Compacting Steel Fiber Reinforced Expanded-Shale Lightweight Concrete under Uniaxial Compression.

To expand the structural application of steel fiber reinforced expanded-shale lightweight concrete (SFRELC), a self-compacting SFRELC with high-workability was developed based on previous research. As part of the investigation, the present study focuses on the adaptability of formulas used for the complete stress-strain curves of steel fiber reinforced lightweight-aggregate concrete and conventional concrete under uniaxial compression. On the basis of mix proportion of SFRELC, self-compacting SFRELC was designed with the volume fraction of steel fiber as 0%, 0.4%, 0.8%, 1.2%, 1.6%, and 2.0%. Eighteen cylindrical specimens with dimensions of Φ150 mm × 300 mm were tested to measure the uniaxial compressive stress-strain curves of self-compacting SFRELC. Results indicated that, with the increasing volume fraction of steel fiber, the compressive strain at the peak-stress of the stress-strain curve increased, while the slope of the descending portion decreased. This increased the energy absorption of self-compacting SFRELC with a higher compression toughness. With a comparison of test results between four groups of calculation models, a group of formulas is selected to express the complete stress-strain curves of self-compacting SFRELC under uniaxial compression.

Behavior of Rectangular-Sectional Steel Tubular Columns Filled with High-Strength Steel Fiber Reinforced Concrete Under Axial Compression.

This paper studies the effect of high-strength steel fiber reinforced concrete (SFRC) on the axial compression behavior of rectangular-sectional SFRC-filled steel tube columns. The purpose is to improve the integrated bearing capacity of these composite columns. Nine rectangular-sectional SFRC-filled steel tube columns and one normal concrete-filled steel tube column were designed and tested under axial loading to failure. The compressive strength of concrete, the volume fraction of steel fiber, the type of internal longitudinal stiffener and the spacing of circular holes in perfobond rib were considered as the main parameters. The failure modes, axial load-deformation curves, energy dissipation capacity, axial bearing capacity, and ductility index are presented. The results identified that steel fiber delayed the local buckling of steel tube and increased the ductility and energy dissipation capacity of the columns when the volume fraction of steel fiber was not less than 0.8%. The longitudinal internal stiffening ribs and their type changed the failure modes of the local buckling of steel tube, and perfobond ribs increased the ductility and energy dissipation capacity to some degree. The compressive strength of SFRC failed to change the failure modes, but had a significant impact on the energy dissipation capacity, bearing capacity, and ductility. The predictive formulas for the bearing capacity and ductility index of rectangular-sectional SFRC-filled steel tube columns are proposed to be used in engineering practice.

Testing and Prediction of the Strength Development of Recycled-Aggregate Concrete with Large Particle Natural Aggregate.

In this paper, a new recycled aggregate concrete (RAC) was produced with composite coarse aggregate and fine recycled aggregate. The composite coarse aggregate was mixed into continuous gradation by large particle natural aggregate with small particle recycled aggregate. To explore the time-dependent developments of the compressive strength and splitting tensile strength of this new RAC, 320 groups of cubic specimens were tested at different curing ages from 3 days to 360 days to measure the compressive and splitting tensile strengths. The amount of large particle natural aggregate varied from zero to 70% in mass of the total coarse aggregate. The water/cement ratio was taken as 0.60, 0.49, 0.41 and 0.36 to represent four strength grades of the RAC at about C20, C30, C40 and C50. Based on the tested results, the curves of the compressive and tensile strengths of the RAC that changed with curing age are plotted, which clearly exhibit that the amount of large particle natural aggregate had a rational range in different strength grades of the RAC which had better aging strength. When the RAC was no larger than C30 with a water/cement ratio of 0.60 and 0.49, the amount of large particle natural aggregate should be no more than 30%; when the RAC was no less than C40 with a water/cement ratio of 0.41 and 0.36, the amount of large particle natural aggregate should be no less than 50%. Along with the general prediction of the strength development of all the tested RAC, the optimal predictive formulas are proposed for the strength development of RAC with a rational amount of natural aggregate. Meanwhile, the strength developments of RAC with a rational amount of natural aggregate are assessed by the time-dependent models proposed by the ACI Committee 209 and CEB-FIP MC 2010.

Experimental Investigation on Columns of Steel Fiber Reinforced Concrete with Recycled Aggregates under Large Eccentric Compression Load.

To improve the structural application of steel fiber-reinforced concrete with recycled aggregates (SFRC-RA) composited in gradation by large-particle natural coarse aggregate and small-particle recycled coarse aggregate, the large eccentric compression behavior of eight SFRC-RA columns was experimentally investigated in this paper. The main parameters considered were the strength of the SFRC-RA and the volume fraction of the steel fiber. Details about the sectional concrete strain, the longitudinal steel bar strain, the lateral displacement, the cracking load, the crack distribution and crack width, and the ultimate load of the SFRC-RA columns were measured. The beneficial effects of steel fiber on these attributes were discussed, and the ductility corresponding to the lateral displacement of the SFRC-RA columns was also analyzed. Based on the test results and design principles, formulas were proposed for predicting the cracking resistance, crack width, and lateral displacement of SFRC-RA columns in a normal service state. The ultimate loads of the SFRC-RA columns under a large eccentric compression load were calculated, considering the second-order effects.

Pharmacokinetics and safety of salbutamol/ambroxol fixed-dose combination granules in healthy Chinese subjects
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OBJECTIVES: The aim of the study was to investigate the pharmacokinetics and tolerability of salbutamol/ambroxol fixed-dose combination granules following single and multiple dosing in healthy Chinese subjects. MATERIALS AND METHODS: This was a randomized, open-label, two-period, one-sequence study (n = 12). Each subject received a single oral dose in period 1 and multiple doses in period 2. Plasma concentrations of these two components were determined using a validated LC-MS/MS method. Adverse events (AEs) were documented throughout the study. Investigators evaluated AEs in terms of frequency, duration, intensity, seriousness, outcome, and relationship to study drugs. RESULTS: Following single dosing, Cmax values were 8.07 ± 1.31 ng/mL and 25.7 ± 6.5 ng/mL for salbutamol and ambroxol, respectively. The corresponding T1/2 values were 8.15 ± 3.13 hours and 9.31 ± 2.27 hours, respectively. Moreover, no statistical differences in the pharmacokinetics of salbutamol and ambroxol in subjects receiving single or multiple dosage were observed. Single- and multiple-dose oral administration of fixed-dose combination granules were safe and well tolerated in healthy Chinese subjects. Drug hypersensitivity syndrome did not occur during our study. CONCLUSION: The pharmacokinetics of salbutamol and ambroxol in the fixed-dose combination granules were not affected by dosing duration, and gender differences seemed to have no effect on the pharmacokinetics of salbutamol and ambroxol after a single dose and multiple doses of the medication.
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