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Cubosomes, as biocompatible carriers in drug delivery systems, consist of curved bicontinuous lipid bilayers. With a honeycombed structure divided into two internal aqueous channels, cubosomes could be used for many bioactive ingredients. Achyranthes bidentata polysaccharides (ABPs) are isolated from the roots of Achyranthes bidentata , used in Chinese herbal medicine, and present a noticeable effect as an immunomodulator. This study investigates the optimal preparation of combined cubosome-ABP (Cub-ABP) nanoparticles using response surface methodology and explores their characteristics and stability. The encapsulation efficiency of optimized Cub-ABPs was 72.59%. In-vitro stability studies demonstrated the stability of Cub-ABPs and cubosome nanoparticles without ABPs; both were stable for up to 25 days. Safe concentrations of Cub-ABPs and cubosome nanoparticles without ABPs are 104.06 μg/mL and 208.13 μg/mL with comparatively low cytotoxicity against lymphocytes. Moreover, the feasible immunomodulatory effects of Cub-ABPs were determined by evaluating their proliferation and change of CD4 + /CD8 + ratio on splenic lymphocytes in vitro . Proliferation and flow cytometry studies revealed that, compared with free ABPs and blank cubosomes, Cub-ABPs proved more effective in promoting lymphocyte proliferation and in triggering the transformation of T-lymphocytes into T h -cells. [ABSTRACT FROM AUTHOR]

1. Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy volunteers. 2. In this open-label, single-dose, randomized and four-period crossover study, 16 healthy Chinese subjects received ilaprazole 5, 10 or 20 mg intravenously, or 10 mg orally. Serial blood and urine samples were collected and intragastric pH was recorded within 24 h. The percentage time of intragastric pH > 6 was the major index. Safety was assessed throughout the study. 3. Plasma exposure of intravenous ilaprazole increased proportionally over the dose of 5–20 mg. Clearance and volume of distribution were independent of dose. Ilaprazole was not eliminated through urine and the absolute bioavailability was 55.2%. For the intravenous dose of 5, 10, 20 mg, and oral dose of 10 mg, the mean percentages time of intragastric pH > 6 were 47.3%, 52.8%, 68.2% and 47.5%, respectively. 4. Ilaprazole showed linear pharmacokinetics over the dose of 5–20 mg. Intravenous ilaprazole provided rapid onset of action and the potency of effect were exhibited in a dose-dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated activated partial thromboplastin time (APTT) and prothrombin time (PT). [ABSTRACT FROM PUBLISHER]

SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a Tmax of approximately 4 hours, and systemic exposure increased with dose. Accumulation was minimal (2- to 3-fold) and steady state was reached after seven days of dosing. For pharmacodynamics, no significant hypoglycaemic effects were seen in healthy adults. Good pharmacokinetics and safety were demonstrated but no obvious effect was found. [ABSTRACT FROM AUTHOR]

Background and Objectives: Ilaprazole is a novel proton pump inhibitor that provides effective and long lasting inhibition of intragastric acid secretion. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of intravenous ilaprazole after multiple administrations in healthy Chinese subjects. Methods: This was an open-label and multiple-dose clinical study. Ten healthy Chinese subjects received 10 mg ilaprazole infusion once daily for 5 days. Helicobacter pylori status was examined. Blood samples were collected and intragastric pH was recorded for 24 h. Safety was assessed throughout the study. Results: There was no accumulation after multiple administrations. The mean steady-state half-life and clearance were comparable to those following single administration. Ilaprazole provided sustainable and significant intragastric pH control in terms of percentage time at pH >4, pH >6 within 24 h and mean 24-h pH values. The pH value within 24 h was affected by Helicobacter pylori infection in subjects with continuous infusion. Intravenous ilaprazole was safe and there were no serious adverse events. Conclusion: Intravenous ilaprazole provided stable pharmacokinetics and pharmacodynamics at a dose of 10 mg once daily for 5 days, and was well tolerated in healthy subjects. [ABSTRACT FROM AUTHOR]

Background: The purpose of this retrospective study was to evaluate and compare the clinical outcomes of patients underwent PVP for OVCF as day surgery with the outcomes of patients managed as traditional inpatients. Methods: According to the selection criteria, patients who underwent PVP for single-segment thoracolumbar OVCF were included retrospectively in the day surgery procedure (DSP) group and the traditional inpatient procedure (TIP) group between April 2018 and September 2019. The visual analog scale score (VAS) and Oswestry Disability Index (ODI) score were recorded preoperatively and 1 day, 1 week, 1 month, 3 months, 6 months, and 12 months after surgery. Duration of hospital stay, preoperative waiting time, hospital cost, and postoperative complications were recorded and analyzed. Results: A total of 335 patients (53 in DSP group; 282 in TIP group) were enrolled and completed 12-month follow-up. The mean duration of hospital stay, the mean preoperative waiting time, and the mean hospital costs were significant lower in the DSP group. The postoperative VAS and ODI scores in both groups were significantly improved after surgery. Moreover, both VAS and ODI scores at each follow-up stage were also significantly lower than the previous follow-up stage. However, the ODI score in the DSP group was significantly lower at 1-day, 1-week, 1-month, and 3-month follow-up, respectively. For cement leakage and secondary vertebral compression fractures, there was no statistical difference between the two groups. Conclusions: We suggest that PVP for OVCFs in day surgery procedure is worthy of wide application. [ABSTRACT FROM AUTHOR]

Aims: The objectives were to investigate the pharmacokinetics, pharmacodynamics and safety of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control, and then recommend the dosage regimen for Phase 2b/3 studies. Methods: Three clinical studies were performed. First, 16 healthy subjects received infusion of ilaprazole 30 mg or esomeprazole 80 mg. Second, 12 healthy subjects received ilaprazole 20 mg followed by 10 mg once daily for 2 days. Finally, 20 patients with duodenal ulcers received ilaprazole 20 mg followed by 10 mg for 2 days or esomeprazole 40 mg twice daily for 3 days. Serial blood samples were collected and intragastric pH was recorded. Results: The mean percentages time of intragastric pH >6 was 63.6 and 51.7% for healthy subjects after receiving ilaprazole 30 mg and esomeprazole 80 mg. Linear pharmacokinetics was observed when the dose was increased to 30 mg but the effect was saturated. Ilaprazole 20 mg followed by 10 mg for 2 days provided higher plasma exposure in healthy subjects than patients, but the effect was comparable. After multiple administrations, ilaprazole provided similar effect to esomeprazole. Ilaprazole infusion was safe and well tolerated without serious adverse events. Conclusions: Ilaprazole provided comparable effect of pH control to esomeprazole, with lower dose and fewer times of administration. There was no significant difference of ilaprazole between healthy subjects and patients regarding intragastric acid inhibition. A loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days was recommended for Phase 2b/3 studies. [ABSTRACT FROM AUTHOR]

Wire and arc additive manufacturing (WAAM) is a promising technology for the preparation of refractory metal functional gradient materials (FGMs) due to its high material utilization, high deposition efficiency and ability to create large-sized parts. In the present work, 316L/IN625 FGM with chemical composition gradients of 25 wt% and 100 wt% were fabricated using dual-wire plasma arc additive manufacturing (DW-PAAM) by changing the wire feeding speeds (WFSs) layer by layer. The phase evolution, microstructure, chemical composition and mechanical properties of the FGM were analyzed. The results demonstrated that the microstructure in all regions was predominantly the austenite phase, and no cracks or defects were observed. The microstructure of the 100 wt% 316L zone was composed of the austenite phase (face-centered cubic, FCC) and a small amount of ferrite phase (body-centered cubic, BCC), whereas mainly FCC structure was observed in the other chemical composition regions. There was a certain error between the actual composition gradient and the designed gradient. The microhardness transition of S1 was smoother and wider, while the tensile test results of S2 were better. In addition, the position of the tensile fracture was different for S1 and S2. In conclusion, the DW-PAAM process shows great potential for manufacturing FGM with desirable properties for various industrial applications. Further studies are warranted to optimize process parameters and develop new design strategies to enhance the performance of FGM in various industrial applications. • 316L/IN625 FGM with composition gradients of 25 wt% and 100 wt% were prepared by the DW-PAAM process. • The microstructure in all regions was predominantly the FCC structure, no cracks or defects were observed. • A certain error existed between the chemical composition curve of the actual gradient and the design gradient. • Sample S1 has the lowest microhardness and tensile strength in the zone of 75 wt% 316L. [ABSTRACT FROM AUTHOR]

The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects. A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using non-compartmental method. The maximum concentration (Cmax) and the area under the curve (AUC0-24 h) were all corrected by the dose given. In the wild-type group, the mean dose-corrected AUC0-24 h was 1.35-fold larger than in CYP3A4*1G carriers (p = .018). Among the three CYP3A5 genotypes, there showed significantly difference (p = .008) in the t1/2, but no significant difference was observed for the AUC0-24 h and Cmax. In subjects with the CYP3A5*3/*3 genotype, the mean t1/2 was 1.35-fold higher than in CYP3A5*1/*1 group (p = .007). And the t1/2 in CYP3A5*3 carriers also was 1.32-fold higher than in the wild-type group (p = .004). CYP3A4*1G and CYP3A5*3 polymorphisms may influence tylerdipine pharmacokinetic in healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

Highlights • FT-IR has been employed to characterize the Lycium barbarum polysaccharides (LBP). • LBPL enhanced significantly proliferation effects on mouse DC precursor cells. • LBPL induced DCs maturation characterized by up-regulation co-stimulatory molecules. • Enhanced antigen uptake and production of cytokines in DCs after incubation with LBPL. • The mechanism of TLR4 signaling was involved in LBPL-elicited activation of DCs. Abstract Dendritic cells (DCs) are professional antigen-presenting cells (APC) that play a central role in the initiation and regulation of immune responses. We have previously demonstrated that Lycium barbarum polysaccharides liposomes (LBPL) as immune adjuvant elicits strong antigen-specific Th1 immune responses. The purpose of this study was to investigate underlying mechanism of liposomes promoting effect of Lycium barbarum polysaccharides (LBP) on activating DCs. LBP were loaded with high entrapment efficiency (86%) into liposomes using reverse phase evaporation. LBPL activation of phenotypic and functional maturation of DCs was explored through mechanistic studies of the TLR4-MyD88-NF-κB signaling pathway and amount of proinflammatory cytokines released. We found that LBPL indeed activated immature DCs and induced DCs maturation characterized by up-regulation of co-stimulatory molecules (MHCII, CD80, CD86), production of cytokines (IL-12p40, TNF-α), and enhancement of antigen uptake. Additionally, we demonstrated that liposomes could promote LBP up-regulation of TLR4, MyD88, TRAF6, NF-κB gene and protein expression. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Nanoparticles (NPs)-based vaccine delivery systems are widely used for their ability to control the release of antigens and promote immune responses against cancer or infectious diseases. In this study, the immunopotentiator Angelica sinensis polysaccharide (ASP) and model protein antigen ovalbumin (OVA) were encapsulated into Poly(lactic-co-glycolic acid) (PLGA) to formulate the novel NPs-based vaccine delivery system (ASP-PLGA/OVA). These formulations were subcutaneously administered to mice, then the magnitude and kinetics of antibody and cellular immune responses were assessed. The ASP-PLGA/OVA NPs were pherical in shape with smooth surfaces, approximately 225.2 nm in average size, negatively charged (around −11.27 mV), and the encapsulation efficiency of OVA at around 66.28%, respectively. Furthermore, ASP-PLGA/OVA NPs could keep stable at 4 °C over 30 days and provide a sustained and controlled release of OVA from the NPs. The results demonstrated that mice immunized with ASP-PLGA/OVA NPs could significantly enhance lymphocyte proliferation and improve the ratio of CD4+ to CD8+ T cells, thereby ASP-PLGA/OVA NPs could induce a strong cellular immune response. Moreover, the ASP-PLGA/OVA NPs could induce vigorous and long-term IgG immune responses with a mixed Th1 and Th2 responses and up-regulate the levels of Th-associated cytokines. These results suggested that ASP-PLGA/OVA NPs, which stimulated strong and continuous antibody responses and induced cellular immune responses, could potentially serve as an efficient and safe vaccine delivery and adjuvant system against infections and diseases. [ABSTRACT FROM AUTHOR]

Background and Objective: Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects.Methods: Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study.Results: Following a single oral dose of tylerdipine of 5-30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate.Conclusion: Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5-30 mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing.Study registrations: CTR20140862 and CTR20150660. [ABSTRACT FROM AUTHOR]

Tylerdipine hydrochloride is a novel L‐type and T‐type dual calcium channel antagonist that has the potential effects of expanding blood vessels and lowering blood pressure. It is expected to reduce the side effect of ankle edema observed with other drugs in the same class. A randomized, open‐label, crossover phase 1 study was performed to evaluate the effect of food on the bioavailability of tylerdipine. Fourteen healthy male volunteers were enrolled. The administration of tylerdipine after a high‐fat meal increased the bioavailability of tylerdipine. In the fed state there was a 130% increase in the mean total systemic exposure (AUCinf) and a 73% increase in the mean peak plasma concentration (Cmax) compared with that in the fasting state. The geometric mean ratios (90% confidence interval) of Cmax and AUCinf were 2.54 (1.94, 3.33) and 1.75 (1.50, 2.04) for tylerdipine. The exposures of the 2 main metabolites M2 and M4 were increased by approximately 10% after a high‐fat meal. The median time to peak plasma concentration of tylerdipine showed no difference between fasting and fed states. [ABSTRACT FROM AUTHOR]

Abstract The immunoregulation and immunopotentiation of Polysaccharides of Atractylodes macrocephala Koidz (PAMK) have been widely demonstrated. Nanostructured lipid carriers (NLC) have high drug loading capacity for lipophilic and hydrophilic drugs, and have good biocompatibility and high bioavailability. In this study, the effect of PAKM-NLC on the surface molecule expression of bone marrow-derived dendritic cells (BMDCs) in vitro was investigated by flow cytometry, and the cytokines secreted by dendritic cell supernatants were detected by ELISA. The results showed that compared with other control groups, PAMK-NLC could significantly increase the expression of CD80 and CD86 and promote the secretion of IL-1β, IL-12, TNF-α and IFN-γ, indicating that PAMK-NLC have a more pronounced effect on the maturation and differentiation of BMDCs. In addition, effects of PAMK-NLC nanoparticles on OVA-immunized mice were explored. Compared with other control groups, PAMK-NLC-OVA can significantly promote the production of OVA-specific antibodies in serum, stimulate the secretion of cytokines, increase the proliferation rate of spleen lymphocytes after OVA re-stimulation, and induce stronger activation of CD3+CD4+ and CD3+CD8+ lymphocytes. As an adjuvant of OVA, PAMK-NLC has a better immunological enhancement effect than PAMK or blank NLC, and has good adjuvant activity. [ABSTRACT FROM AUTHOR]

Abstract For quantitative assaying tylerdipine hydrochloride, and its two primary metabolites (M2 and M4) in human urine, two sensitive and accurate LC-MS/MS methods were firstly developed and validated, where multiple reaction monitoring (MRM) was applied under positive electrospray ionization mode for tylerdipine and negative electrospray ionization mode for M2/M4, respectively. Urinary proteins were precipitated using acetonitrile, and deuterated isotopes of tylerdipine and M4 ([D5]‑tylerdipine and [D6]-M4) were used as internal standards. Triton X-100, a good surfactant, was used to prevent the adsorption. An Agilent Poroshell 120 column was employed for chromatographic separation of the analytes with the mobile phases of 2 mM ammonium formate solution (containing 0.1% formic acid) and acetonitrile (45:55 for tylerdipine and 75:25 for the M2/M4, v/v). Flow rate was 0.3 mL/min. Calibration curves for tylerdipine, M2 and M4 in urine were linear over the ranges of 0.02–10 ng/mL, 2–1500 ng/mL and 0.5–200 ng/mL, respectively. The precision, accuracy, specificity and stability of two methods all evaluated and achieved the acceptable criteria. The LC-MS/MS methods were successfully applied to assay urinary excretion of tylerdipine and the metabolites in healthy Chinese subjects who orally received a single dose of 20 mg tylerdipine tablet. Generally, the urinary excretion of the two primary metabolites accounted for 11.7% of the total dose of tylerdipine in healthy Chinese subjects, while little tylerdipine was recovered in urine. Highlights • LC-MS/MS methods were firstly developed and validated for assaying urinary tylerdipine and its two metabolites in human. • The methods were applied to evaluate urinary excretion of tylerdipine and its two metabolites in healthy Chinese subjects. • The urinary excretion of the two metabolites accounted for 11.7%, while little tylerdipine was recovered in human urine. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation. [ABSTRACT FROM AUTHOR]

In this study, angelica sinensis polysaccharide (ASP) was encapsulated into the Poly (lactic-co-glycolicacid) (PLGA) to constitute the ASP-PLGA. The aim of the study is to obtain optimal encapsulation efficiency of ASP-PLGA by optimizing the preparation conditions and investigate the immunological enhancement activity of ASP-PLGA. To obtain the optimal processing parameters, the parameters, such as the ratio of organic phase (o) to internal water phase (w 1 ), the ratio of external water phase (w 2 ) to organic phase (o) and the concentration of Pluronic F68 (F68) (w/v) were examined through response surface methodology (RSM). The optimum preparation conditions of ASP-PLGA for maximizing encapsulation efficiency (EE) was as follows:ratio of organic phase (o) to internal water phase (w 1 ) at 10:1, ratio of external water phase (w 2 ) to organic phase (o) at 11:1, the concentration of F68 at 0.8% and the experimental EE 67.89 ± 0.48% was achieved. In addition, the results showed that ASP-PLGA could significantly promote the lymphocytes proliferation and increase the ratio of CD4 + to CD8 + T cells compared with ASP and blank PLGA. This study provided strong evidence that the immunological enhancement of ASP was significantly improved through establishing a drug delivery system with PLGA. [ABSTRACT FROM AUTHOR]

Purpose: Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men.Methods: Six subjects were administrated an oral suspension containing 5 mg of 14C-labeled HMPL-013 (100 μCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses. Safety assessments were conducted throughout the study.Results: Over a 336-h post-dose collection period, mean recovery was 90.11% of the radiolabeled dose, with 60.31% in urine and 29.80% in feces. Mean C max, AUC0-∞, and T max for HMPL-013 in plasma were 113 ng/mL, 4797 h ng/mL, and 2 h, respectively. Radioactivity and HMPL-013 were cleared from circulation with terminal half-lives of 41.1 and 33.4 h. HMPL-013 was the predominant circulating radioactive component, representing 72.48% of the total radioactivity. M11 was the major circulating metabolite, accounting for 17.31% of the total radioactivity. An additional seven circulating metabolites were identified, each accounting for less than 5% of the total radioactivity. In urine, HMPL-013 accounted for only 0.50% of the administered dose. Three major metabolites M285, M381, and M409-4 were identified in urine accounting for 10.48, 21.16, and 8.92% of the dose, respectively. In feces, HMPL-013 accounted for 5.34% of the dose. M205, M365-2, and M380 were the major metabolites, accounting for 2.29, 3.30, and 2.59% of the dose, respectively.Conclusion: HMPL-013 was well tolerated and absorbed rapidly, with parent compound being the predominant circulating component. HMPL-013 was extensively metabolized prior to excretion, and urine was the major route of excretion. [ABSTRACT FROM AUTHOR]

Purpose: Ginkgo terpene lactones meglumine injection (GMI) is a novel preparation of traditional Chinese medicine that contains ginkgolides A, B and K (GA, GB, GK, respectively) as its primary components. In this study we evaluated the safety, tolerability and pharmacokinetics of these three ginkgolides after single and multiple intravenous infusions of GMI. We also investigated the effect of GMI on cytochrome P450 3A4 (CYP3A4) in healthy Chinese volunteers. Methods: In this open-label, placebo-controlled study 15 subjects were randomly assigned to receive GMI or matched placebo (4:1 ratio). All subjects first received midazolam (MDZ) on day 1, followed by a 6-day washout. On Day 8, the subjects were started on once-daily dosing of either GMI or placebo for 14 days. Lastly, on Day 22 the subjects were given second dose of MDZ + GMI or MDZ + placebo. Plasma concentrations of ginkgolides, MDZ and its metabolite 1-hydroxy midazolam were quantified. Results: The steady-state conditions of GA, GB and GK were achieved after 6 days of daily dosing. Following a single dose of GMI (Day 8) the area under the concentration-timecurve from zero to 24 h after administration (AUC) of GA, GB and GK (arithmetic ± standard deviation) was 4.10 ± 1.06, 4.61 ± 1.31 and 0.127 ± 0.102 h μg/mL, respectively; the corresponding values following multiple doses of GMI (Day 19) were 3.94 ± 1.16, 5.00 ± 1.55 and 0.118 ± 0.096 h μg/mL, respectively. The mean accumulation ratios were 0.95, 1.08 and 0.89 for GA, GB and GK, respectively. Additionally, the geometric mean [peak concentration (C) and AUC] ratios of MDZ and 1-hydroxy midazolam were all within the specified acceptance ranges in the MDZ + placebo treatment and MDZ + GMI treatment. Conclusions: Our results show that GMI was well tolerated during the entire study. There was no systemic accumulation and no significant effects on the pharmacokinetics of MDZ in healthy Chinese male subjects after repeated dosing of GMI. [ABSTRACT FROM AUTHOR]

Powder plasma arc additive manufacturing (PPA-AM) is a promising method for the preparation of high-entropy alloys (HEAs), and has the advantages of low cost, high efficiency, and high quality. In this study, the CoCrFeNiW x (x = 0, 0.2, 0.5, 0.7, and 1.0) HEAs were successfully prepared via the PPA-AM technique. Microstructure and mechanical properties of alloys with different W content were investigated. The results showed that the microstructure changed from a single FCC phase (x = 0) to the dual-phase FCC + µ (x = 0.2 and 0.5), and then to a three-phase combination of FCC + µ + BCC (x = 0.7 and 1.0) with the addition of W. The volume fraction of the µ phase and BCC phase increases with the increase in W content, while the size of FCC columnar grain is significantly reduced. The solid-solution strengthening of the FCC phase and the second phase strengthening were mainly responsible for the increase in the microhardness (136–413 HV) and yield strength (187–567 MPa) while the brittleness of the μ phase contributes to the expansion of the crack, which leads to a decrease in the ductility (50.8% to 0.3%). These results can provide a systematic understanding of the phase transformation of PPA-AM HEAs with different W content and its effects on the mechanical properties. • Powder plasma arc additive manufacturing (PPA-AM) of CoCrFeNiWx high-entropy alloys. • PPA-AM can produce high-entropy alloys with lower cost and high efficiency. • The microstructure and mechanical properties of the CoCrFeNiWx HEAs were investigated. • W element can promote the phase transformation from FCC phase to µ and BCC phase. • The strength of the HEAs was significantly improved with addition of W. [ABSTRACT FROM AUTHOR]

Powder plasma arc additive manufacturing (PPA-AM) is a promising method for fabricating high-entropy alloys (HEAs). However, the characteristics of thermal cycling during the PPA-AM process and the mechanism of subsequent heat treatment on the microstructure and mechanical properties are unclear. In this study, an Al 1.2 CoCrFeNi 2.1 HEA with dual-phase (FCC + B2) was fabricated via PPA-AM. The microstructure and mechanical properties of the as-built and heat-treated samples were explored. The crystallographic orientations of the FCC and B2 phases were also determined. Because the alloy in the bottom region was affected by thermal cycling, B2 particles precipitated in the FCC phase, and FCC particles precipitated in the B2 phase. During the tensile test, the phase boundary between B2 matrix and FCC particles produced cracks preferentially. These cracks reduced the strength and elongation of the alloy. After heat treatment at 1200 °C, the FCC and B2 precipitates formed globular shapes inside the B2 and FCC grain matrix, respectively. The alloy showed a uniform structure and the ductility of the alloy was improved significantly. This work elucidates the mechanisms of thermal cycling and heat treatment on the microstructure and mechanical properties of the alloy. [ABSTRACT FROM AUTHOR]

• AlCoCrFeNi 2.1 high-entropy alloy was fabricated by PPA-AM method. • The B2 phase precipitates at the bottom region of the HEA due to thermal cycling. • The ductility of the HEA increases and the strength decreases due to thermal cycling. High-entropy alloys (HEAs) are a novel class of materials. In this study, the AlCoCrFeNi 2.1 HEA was prepared using powder plasma arc additive manufacturing (PPA-AM). The influence of thermal cycling in the PPA-AM process on AlCoCrFeNi 2.1 HEA was investigated. The AlNi elements in the FCC phase in the bottom region were aggregated by thermal cycling to form the acicular B2 particles. This weakened the solid solution strengthening effect of the FCC phase, reduced its yield strength (421 to 389 MPa), and improved its ultimate tensile strength (929 to 981 MPa) and elongation (15.6 % to 21.0 %). The results of this study might have reference significance for the AlCoCrFeNi alloy system. [ABSTRACT FROM AUTHOR]

High-entropy alloys (HEAs) are promising coating materials for wear resistance applications. However, the preparation of HEA coatings with powder has the disadvantages of high cost and low efficiency. In this study, an innovative triple-wire plasma arc cladding (TW-PAC) method was used to prepare HEA coatings. Nonequiatomic Cr-Fe-Ni-Ti x (x is Ti wire feeding speed, x = 0, 0.5, 0.8 and 1.0 m/min, denoted as Ti 0 , Ti 0.5 , Ti 0.8 and Ti 1.0) HEA coatings were successfully prepared by using three commercial wires (ERTi-2, ER304L and Cr 20 Ni 80 wire). With increasing Ti content, the structure of the Cr-Fe-Ni-Ti x HEA coatings changed from the single FCC phase to the FCC + γ′ (Ni 3 Ti) + Laves (Fe 2 Ti) phase, and the microhardness of the coatings increased from 137 HV to 873 HV. Due to the addition of Ti, Ni 3 Ti and Fe 2 Ti phases with high hardness precipitated in the alloy coating, accompanied by the solid solution strengthening effect of the FCC phase, the wear resistance of the coatings was significantly improved (from 9.67 × 10−4 to 1.49 × 10−4 mm3/N·m). The results of this study contribute to the preparation of thick HEA coatings overlarge areas at low cost and with high efficiency and provide new insights into Cr-Fe-Ni-Ti x HEA coatings. • Triple-wire plasma arc cladding (TW-PAC) of Cr-Fe-Ni-Tix high-entropy alloy coatings. • High-entropy alloy coatings were prepared using three commercial wires. • The phase of the coatings changed from FCC to FCC + Ni 3 Ti + Fe 2 Ti with the addition of Ti. • The wear resistance of the coatings was significantly improved with addition of Ti. [ABSTRACT FROM AUTHOR]

l-Valine, l-leucine, l-isoleucine, l-phenylalanine, and l-tyrosine are important proposed biomarkers for the early detection and diagnosis of type 2 diabetes. A simple and selective hydrophilic interaction chromatography with tandem mass spectrometry method was developed for the simultaneous determination of these amino acids in human serum, using stable isotope-labeled amino acids as internal standards. Chromatographic separation was carried out on a Syncronis HILIC column (150 mm × 2.1 mm, 5 μm) with the column temperature of 35°C and a mobile phase consisted of acetonitrile/120 mM ammonium acetate (89:11, v/v), and the run time was 11.0 min. The mass spectrometric analysis was performed using a QTRAP 5500 mass spectrometer coupled with an electrospray ionization source in positive ion mode. As these five amino acids are endogenous compounds in serum, we used the corresponding stable isotope-labeled amino acids to evaluate the matrix effect and recovery in serum. The matrix effect was 98.7-107.3%, and the recovery was 92.7-102.3%. Calibration curves spiked unlabeled amino acids in water were linear over the range of 0.200-100 μg/mL. The accuracy, inter-, and intraday precision were below 10.2%. Analytes were stable during the study. This assay method has been validated and applied to the early diagnosis research of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sitafloxacin is a new fluoroquinolone antimicrobial agent with high activity. In this article, we reported a simple, rapid and specific LC–MS/MS method for accurate determination of sitafloxacin concentrations in human urine from healthy volunteers in detail. A two-step dilution method for the analysis of sitafloxacin in human urine using LC coupled to positive MS/MS has been developed and validated according to US FDA guidelines and Chinese State Food and Drug Administration (CFDA) guidelines for the validation of bioanalytical methods. The method uses 50 μL of urine and covers a working range from 0.025 to 20 μg/mL with a LLOQ of 0.025 μg/mL. This new LC–MS/MS assay is sensitive and specific. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to develop a rapid and sensitive method for the simultaneous quantification of metronidazole (MEZ), tinidazole (TNZ), ornidazole (ONZ) and morinidazole (MNZ) in human saliva. A reversed-phase high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection at 318nm was carried out on a C18 column, using a mixture of potassium dihydrogen phosphate buffer, acetonitrile, and methanol (55:15:30, v/v/v) as a mobile phase with a flow rate of 1.0ml/min. The saliva samples (100μl) were firstly deproteinized by precipitation with methanol (400μl), after which they were centrifuged and the supernatants were directly injected into the HPLC system. This method produced linear responses in the concentration ranges of 25.2–5040.0, 23.9–4790.0, 25.4–5080.0, 25.0–5000.0ng/ml with detection limits of 6.0, 17.6, 10.0 and 11.3ng/ml for MEZ, TNZ, ONZ and MNZ (S/N=3), respectively. The methods were validated in terms of intra- and inter-batch precision (within 7.3% and 9.1%, respectively), accuracy, linearity, recovery and stability. The study proved that HPLC is both sensitive and selective for the simultaneous quantification of MEZ, TNZ, ONZ and MNZ in human saliva using a single mobile phase. [Copyright &y& Elsevier]

Objectives: To investigate the pharmacokinetics and pharmacodynamics of rabeprazole (RPZ) given as successive intravenous infusion to healthy Chinese volunteers. Methods: A total of 63 subjects (33 males and 30 females) were recruited at four research centers and given a 5-day therapeutic course of RPZ (10, 20, or 40 mg) administered as single daily doses during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 330, 360, or 420 min post-RPZ administration. Intragastric pH was recorded 24 h post-RPZ administration on day 1 and day 5. Results: After receiving a single and repeated doses of RPZ, the area under the plasma concentration-time curve (AUC) was 51.9 ± 22.1, 96.7 ± 27.6, and 188.4 ± 65.8 mg·min/L on day 1 and 59.3 ± 23.9, 106.7 ± 27.8, and 200.3 ± 79.0 mg·min/L on day 5 for the low-, middle-, and high-dose groups, respectively. The corresponding peak concentrations (C) were 0.64 ± 0.11, 1.30 ± 0.26, and 2.6 ± 0.54 μg/mL on day 1 and 0.76 ± 0.15, 1.39 ± 0.25, and 2.91 ± 0.53 μg/mL on day 5, respectively. Although the mean AUC and C values increased from a single dose to repeated doses in the three groups, the difference was not significant. The mean AUC and C ratios of repeated dose to single dose were 1.14, 1.10, and 1.06 on day 1 and 1.19, 1.07, and 1.12 on day 5 for the low-, middle-, and high-dose groups, respectively. After administration of a single dose, the 24-h pH value was significantly higher in the high-dose group than in the low-dose group. After repeated doses, significant increases in pH were observed in the low-, middle-, and high-dose groups; however, the between-group differences were not statistically significant. Conclusions: There is a relationship between the pharmacokinetics and pharmacodynamics of RPZ, with the latter depending in part on the duration of administration, as evidenced by a higher AUC or C and intragastric pH from repeated dosing. [ABSTRACT FROM AUTHOR]

To explore the effect of cytochrome P450 2C19 (CYP2C19) polymorphisms on the relationship between the pharmacokinetics and pharmacodynamics of omeprazole administered by intravenous successive infusions in Chinese healthy volunteers. A total of 21 subjects [7 homozygous extensive metabolizers (homEMs), 9 heterozygous extensive metabolizers (hetEMs), 5 poor metabolizers (PMs)] received a 5-day course of omeprazole (40 mg) administered as a single dose daily during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 8.5 h post-omeprazole administration and at 24 h post-administration, and intragastric pH was recorded on days 1 and 5. After a single dose, both the area under the plasma concentration–time curve (AUC) and peak concentration (Cmax) were higher in PMs than in EMs. Both the mean half-life (t½) and total clearance in PMs were significantly higher and lower than those in homEMs and EMs, respectively. Mean AUC and Cmax ratios in homEMs, hetEMs, and PMs were 1.0:1.1:1.4 and 1.0:1.0:1.1, respectively. Relative to the values determined after a single dose in EMs, after repeated doses, the intragastric pH, AUC, Cmax, and t½ had increased significantly, while the total clearance had decreased significantly. Mean AUC and Cmax ratios in homEMs, hetEMs, and PMs were 1.4:1.4:1.5 and 1.2:1.2:1.3, respectively, compared to those of a single dose. The mean intragastric pH was significantly higher in PMs than in EMs after the fifth dose. There is a relationship between the pharmacokinetics and pharmacodynamics of omeprazole, with the latter depending in part on the duration of administration as evidenced by a higher AUC or Cmax and intragastric pH resulting from repeated dosing. [ABSTRACT FROM AUTHOR]

Abstract: A specific and sensitive liquid chromatography electrospray ionization tandem mass spectrometric (LC–ESI-MS/MS) method for quantitative determination of sertaconazole in human plasma was developed. The analysis was performed and validated in positive ion multiple reactions monitoring mode using loratadine as an internal standard (IS). Sample preparation involved one-step liquid–liquid extraction using ether–dichloromethane (80/20, v/v). Sertaconazole and IS was separated on a C18 column using isocratic elution with a mobile phase of methanol: 0.2% formic acid aqueous solution (70:30, v/v,) at the flow rate of 0.2mL/min. The transition monitored were m/z 439 [M+H]+ → m/z 181 for sertaconazole and m/z 383[M+H]+ → m/z 337 for IS. The lower limit of quantification was 0.1ng/mL based on 500μL of plasma, and no interferences were detected in chromatograms. Calibration curve was linear over the range of 0.1–10ng/mL, and correlation coefficients were 0.999. Intra- and inter-day assay variations were <10%, and the accuracy values were between −0.4% and 9.0% relative error (RE). The extraction recoveries ranged from 60% to 70% across the calibration curve range. The described method provides a sensitive analytical tool to determine sertaconazole in plasma, and was successfully applied to a pharmacokinetic study in 10 healthy human subjects after administration of 300mg vaginal suppository formulation of sertaconazole nitrate. [Copyright &y& Elsevier]