Rigidifying Cation-Tunable Nickel Catalysts Increases Activity and Polar Monomer Incorporation in Ethylene and Methyl Acrylate Copolymerization.

In this study, we synthesized and characterized two nickel complexes featuring conformationally rigid bisphosphine mono-oxide ligands, where one has an o-methoxyphenyl (Ni2) and the other has an o-(2-methoxyethoxy)phenyl (Ni3) substituent on the P═O moiety. We performed metal binding studies using Ni3 and found that its reaction with Li+ and Na+ most likely produced 1:1 and 1:1/2:1 nickel:alkali species in solution, respectively. The nickel complexes were competent catalysts for ethylene homopolymerization and copolymerization, with activities up to 3.8 × 103 and 8.1 × 10 kg mol-1 h-1, respectively. In reactions of ethylene with methyl acrylate (1.0 M), the addition of Li+ to Ni3 led to a 5.4-fold enhancement in catalyst activity and a 1.9-fold increase in polar monomer incorporation in comparison to those by Ni3 alone under optimized conditions. A comparison with other nickel catalysts reported for ethylene and methyl acrylate copolymerization revealed that our nickel-alkali catalysts are competitive with some of the most efficient Ni-based systems developed thus far.

Exosomes secreted from mutant-HIF-1α-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit.

Mesenchymal stem cells (MSCs)-derived exosomes exhibit protective effects on damaged or diseased tissues. Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in bone development. However, HIF-1α is easily biodegradable under normoxic conditions. The bone-marrow-derived mesenchymal stem cells (BMSCs) were transfected with adenovirus carrying triple point-mutations (amino acids 402, 564, and 803) in the HIF-1α coding sequence (CDS). The mutant HIF-1α can efficiently express functional proteins under normoxic conditions. To date, no study has reported the role of exosomes secreted by mutant HIF-1α modified BMSCs in the recovery of the early steroid-induced avascular necrosis of femoral head (SANFH). In this study, we firstly analyzed exosomes derived from BMSCs modified by mutant (BMSC-ExosMU ) or wild-type HIF-1α (BMSC-ExosWT ). In vitro, we investigated the osteogenic differentiation capacity of BMSCs modified by BMSC-ExosMU or BMSC-ExosWT , and the angiogenesis effects of BMSC-ExosMU and BMSC-ExosWT on human umbilical vein endothelial cells (HUVECs). Besides, the healing of the femoral head was also assessed in vivo. We found that the potential of osteogenic differentiation of BMSCs treated with BMSC-ExosMU was higher than the wild-type group in vitro. In addition, BMSC-ExosMU stimulated the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Compared with the BMSC-ExosWT or PBS control group, the injection of BMSC-ExosMU into the necrosis region markedly accelerated the bone regeneration and angiogenesis, which were indicated by the increased trabecular reconstruction and microvascular density. Taken together, our data suggest that BMSC-ExosMU facilitates the repair of SANFH by enhancing osteogenesis and angiogenesis.

Fine-Tuning Nickel Phenoxyimine Olefin Polymerization Catalysts: Performance Boosting by Alkali Cations.

To gain a better understanding of the influence of cationic additives on coordination-insertion polymerization and to leverage this knowledge in the construction of enhanced olefin polymerization catalysts, we have synthesized a new family of nickel phenoxyimine-polyethylene glycol complexes (NiL0, NiL2-NiL4) that form discrete molecular species with alkali metal ions (M(+) = Li(+), Na(+), K(+)). Metal binding titration studies and structural characterization by X-ray crystallography provide evidence for the self-assembly of both 1:1 and 2:1 NiL:M(+) species in solution, except for NiL4/Na(+) which form only the 1:1 complex. It was found that upon treatment with a phosphine scavenger, these NiL complexes are active catalysts for ethylene polymerization. We demonstrate that the addition of M(+) to NiL can result in up to a 20-fold increase in catalytic efficiency as well as enhancement in polymer molecular weight and branching frequency compared to the use of NiL without coadditives. To the best of our knowledge, this work provides the first systematic study of the effect of secondary metal ions on metal-catalyzed polymerization processes and offers a new general design strategy for developing the next generation of high performance olefin polymerization catalysts.

Spatial patterns, factors, and ethnic differences: A study on ethnic minority villages in Yunnan, China.

This paper takes ethnic minority villages in Yunnan province of China, which have significant characteristics of multi-ethnic integration, as the research object. Through various spatial statistical analysis methods, we analyzed the overall distribution characteristics of ethnic villages in Yunnan, the distribution difference among various ethnic groups, and the influencing factors of the distribution pattern. It was found that: (1) The ethnic minority villages in Yunnan generally exhibit a kernel density characteristic of "three concentrated areas and multiple scattered points" and distribution characteristic of "hot spots in the west and cold spots in the east". Each ethnic group has a relatively concentrated region, presenting significant ethnic autocorrelation. (2) The differences in the relationship between villages and landscape among various ethnic groups have given rise to a unique three-dimensional distribution pattern, which is relate to ethnic origin and livelihood culture. Meanwhile, Han traditional villages tend to occupy areas with relatively better geographical conditions. (3) Natural factors, such as topographic relief, the distance between ethnic villages and rivers, and elevation, have a significant impact on the distribution of ethnic villages in Yunnan. Meanwhile, test results of social and human factors, including the distance from central cities, per capita GDP, and the gross annual output values of primary industry, indicate that the development of social economy and the promotion of urbanization pose challenges to the preservation of ethnic villages.

Natural and anthropogenic factors regulating fluoride enrichment in groundwater of the Nansi Lake Basin, Northern China.

Excess fluoride (F-) in groundwater can be hazardous to human health of local residents who rely upon it. Beside natural sources, anthropogenic input may be an additional source to be considered. Twenty surface water and 396 groundwater samples were collected from the Nansi Lake Basin, with hydrogeochemical and isotope techniques employed to clarify the spatial variability, source, and the natural and anthropogenic factors regulating the occurrence of high F- groundwater. The factors responsible for elevated F- levels in surface water and deep confined aquifers are discussed based on their hydraulic relationship. Also a conceptual model of F- enrichment with different aquifer systems is put forward based on the geomorphic units of the basin. The results show that F- concentration is between 0.1 and 6.9 mg/L in the west of Lake, while ranged from 0.03 to 1.74 mg/L in the east of Lake. The hydrogeological setting and lithology are the primary factor determining the provenance of high-fluoride groundwater in the basin. Fluoride mainly originated from the dissolution of fluorine-bearing minerals, and is affected by the alkaline groundwater environment, cation exchange, adsorption, and evaporation. The landforms on the east side of Nansi Lake are low hills and piedmont sedimentary plains, where the aquifers consist of karst fissure water and overlying porewater. High F- groundwater is not observed in this area due to its rapid flow and Ca2+-enriched hydrochemical characteristics. The anthropogenic input (such as fertilizer application on farms and illegal industrial pollutant discharge), contribute F- to groundwater in varying degrees, especially in the shallow aquifers east of the lake and in some parts west of the lake. This work is a clear example of how natural processes together with human activities can affect the chemical quality of groundwater, which is essential to safeguard the sustainable management of water resources in semi-arid areas.

MiR-142-3p as a potential prognostic biomarker for esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: microRNAs (miRNAs), small non-coding RNAs, are always aberrantly expressed in many diseases including human cancers. The aim of this study was to examine and determine the clinical significance of hsa-miR-31, hsa-miR-142-3p, hsa-miR-338-3p, and hsa-miR-1261 expression in esophageal squamous cell carcinoma (ESCC). METHODS: Expression levels of four selected miRNAs, initially evaluated by microarray, were validated by qRT-PCR. Various statistical methods were used to analyze the relationship between miRNA expression and clinicopathologic features and prognosis in 91 patients with ESCC. RESULTS: MiR-31 and miR-142-3p expression were correlated to histological differentiation in ESCC (P < 0.05, Student's t-test); high miR-142-3p expression was associated with a poor prognosis in all 91 ESCC patients (P = 0.014, log-rank) and identified as an independent prognostic factor in ESCC (P = 0.017, univariate Cox; P = 0.022, multivariate Cox). More importantly, stratified analysis indicated that high miR-142-3p expression was correlated to a poor prognosis within good-prognosis groups comprised of ESCC patients with small tumor size, negative lymph node metastasis, or early stage (all P < 0.05). CONCLUSION: The main findings suggest that miR-142-3p is involved in the progression of ESCC and is a potential prognostic biomarker for ESCC.

An online participatory system for SWMM-based flood modeling and simulation.

In the context of the continuous development of urbanization and global climate change, urban flooding risk has become a well-publicized research issue. The Storm Water Management Model (SWMM) performs very well in urban rain-runoff simulations and is widely used to build flood models in specific areas. Because of the complicated and tedious processing work for urban flood modeling and simulation, multifield participants' cooperation is becoming a trend. To promote the research and application of flood modeling and simulation, some resource sharing-oriented systems and platforms have been proposed with the advantages of network technology. However, they still require a participatory environment that can help modeling participants overcome the difficulties of distributed cooperation in the process of SWMM-based flood modeling and simulation. Therefore, we designed and implemented an online participatory system to coordinate the effective collaboration of modeling participants in this process. By referring to the scenarios and specific participatory demands in the modeling process, the system provides a guiding framework that consists of multiple participatory activities and prepares a series of online auxiliary tools designed for these activities. Using the main urban area of Lishui City as the study area, it was confirmed that the process of SWMM-based flood modeling and simulation can be demonstrated collaboratively on the online participatory system developed in this study.

Modulation of pharmacokinetics of theophylline by antofloxacin, a novel 8-amino-fluoroquinolone, in humans.

AIM: To evaluate the pharmacokinetic interactions between theophylline and antofloxacin in vivo and in vitro. METHODS: A randomized, 5-day treatment and 3-way crossover design was documented in 12 healthy subjects. The subjects were orally administered with antofloxacin (400 mg on d 1 and 200 mg on d 2 to 5), theophylline (100 mg twice a day and morning dose 200 mg on d 1 and 5), or theophylline plus antofloxacin. The plasma and urinary pharmacokinetics of antofloxacin and theophylline were characterized after the first and last dose. The effect of antofloxacin on theophylline metabolism was also investigated in pooled human liver microsomes. RESULTS: The 5-day treatment with antofloxacin significantly increased the area of the plasma concentration-time curve and peak plasma concentration of theophylline, accompanied by a decrease in the excretion of theophylline metabolites. On the contrary, theophylline did not affect the pharmacokinetics of antofloxacin. In vitro studies using pooled human hepatic microsomes demonstrated that antofloxacin was a weak reversible and mechanism-based inhibitor of CYP1A2. The clinical interaction between theophylline and antofloxacin was further validated by the in vitro results. CONCLUSION: The results showed that antofloxacin increases the plasma theophylline concentration, partly by acting as a mechanism-based inhibitor of CYP1A2.

The expression of CFL1 and N-WASP in esophageal squamous cell carcinoma and its correlation with clinicopathological features.

Cofilin1 (CFL1) is an actin-modulating protein, which belongs to the ADF/Cofilin family. Neural Wiskott-Aldrich syndrome protein (N-WASP) is the key regulator of the actin cytoskeleton, a member of Wiskott-Aldrich syndrome protein family. They have been suggested to be involved in cancer cell invasion and metastasis. In this study, the expression patterns of CFL1 and N-WASP in normal esophageal mucosa and esophageal squamous cell carcinoma (ESCC) and their correlation with clinical characteristics were investigated. Immunohistochemical staining showed that CFL1 was expressed in nuclear and cytoplasm of cancer cells. However, N-WASP was mainly found in the cytoplasm of the cancer cells. There were significant evidences that proved that CFL1 is correlated with clinicopathological factors in ESCC, such as infiltration depth, lymph node metastasis and pathological staging (P < 0.05). It is also proved that N-WASP is related to lymph node metastasis and pathological staging in ESCC (P < 0.05). Kaplan-Meier analysis showed that there was no correlation between CFL1 and N-WASP protein expression and survival (P > 0.05). Moreover, the mRNA expression of CFL1 and N-WASP was detected by quantitative real time PCR in 70 tissue specimens. The results showed that CFL1 mRNA level was over-expressed in ESCC tissue (P < 0.05), while N-WASP mRNA expression level was not different between cancerous tissues and adjacent normal esophageal mucosa (P > 0.05). Also, CFL1 mRNA expression was significantly associated with regional lymph node metastasis and pathological staging (P < 0.05). Kaplan-Meier analysis showed that there was no correlation between CFL1 and N-WASP mRNA expression and survival (P > 0.05). Our findings suggested that CFL1 and N-WASP may play an important role in the tumorigenesis of ESCC, and to be the candidate novel biomarkers for the diagnosis and prognosis of ESCC. These findings may have implications for targeted therapies in patients with ESCC.

Polymorphisms of HLA-A and HLA-B genes in genetic susceptibility to esophageal carcinoma in Chaoshan Han Chinese.

Esophageal carcinoma (EC) occurs at high rate in Chaoshan region of southern China. Human leukocyte antigen (HLA) polymorphism has been implicated in risk for various cancers. To investigate the impact of HLA-A and HLA-B polymorphisms on susceptibility to EC, a case-control study was conducted among 206 patients with esophageal squamous cell carcinoma and 524 controls from Chaoshan Han population. HLA-A and HLA-B polymorphisms were genotyped by polymerase chain reaction-sequence-specific primers. Genotypic association tests for dominant, recessive, and additive models, and haplotypic association were calculated using unconditional logistic regression. A*11 was identified in a recessive model as an only allele strongly associated with EC risk (odds ratios [OR]=2.10, 95% confidence interval [CI]=1.33-3.31) even after correction for multiple test. The haplotypes A*02-B*46 (OR=1.53, 95% CI=1.04-2.24) and A*11-B*51 (OR=2.29, 95% CI=1.20-4.40) showed association with increased risk for EC, whereas A*11-B*58 (OR=0.00, 95% CI=0.00-0.82) was associated with decreased risk, though the significance of these haplotypes was lost after correction. This is a first association study at genetic level identifying HLA-A and HLA-B-related variations in genetic susceptibility to EC among Chaoshan population. The variation pattern is likely to be EC-specific because it is different from that observed for nasopharyngeal carcinoma in the same study population and might, at least in part, explain the high rate of EC in this ethnic group.

Different Associations Between the IREB2 Variants and Chronic Obstructive Pulmonary Disease Susceptibility.

Background: Iron responsive element binding protein 2 (IREB2) variants may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Recently, many studies have been performed on IREB2 susceptibility variants, including rs2568494, rs2656069, rs10851906, rs12593229, and rs13180, associated with COPD. However, inconsistent findings have been reported. The aim of our research was to determine the association of IREB2 SNPs with COPD. Methods: A comprehensive meta-analysis was performed to accurately estimate the association between IREB2 variants and COPD among four different genetic models. Results: This meta-analysis included a total of 4,096 patients and 5,870 controls. Here, we investigated the 5 IREB2 variants to identify COPD risk. Our results indicate that rs2568494 was associated with an increased risk of COPD for the dominant model (AA+GA vs. GG: OR = 1.150, 95% CI: 1.5-1.304, P = 0.029); rs2656069 was associated with a decreased risk of COPD for the recessive model (GG vs. AA+AG: OR = 0.589, 95% CI: 0.440-0.789; P = 0.000), additive model (GG vs. AA: OR =0.641, 95% CI: 0.441-0.931; P = 0.020), and allele model (G vs. A: OR = 0.812, 95% CI: 0.668-0.988; P = 0.037); and rs10851906 was associated with a decreased risk of COPD for the recessive model (GG vs. AA+AG: OR = 0.732, 95% CI: 0.560-0.958; P = 0.023) and additive model (GG vs. AA: OR = 0.777, 95% CI: 0.637-0.947; P = 0.012). Conclusion: Our findings suggest that the IREB2 rs2568494 minor alleles A may be a genetic factor in susceptibility to COPD. In addition, the minor alleles G of rs2656069 and rs10851906 appear to have a protective effect.

Theoretical model investigating the magnetic properties of cobalt-doped ZnO.

We propose a theoretical model to investigate the magnetic properties of cobalt-doped ZnO (ZnO:Co) thin films qualitatively. The model was built on the dilute Co dopants in the host of ZnO forming the magnetic Co+2 ions and the energy level of the magnetic ions crossing the band edge of ZnO resulting in a magnetic interaction between the Co+2 spins and the spins of the electrons from the conduction band of ZnO. The mechanism of the ferromagnetism revealed in the studied system is proposed here to be induced not only by the mediated conducting electrons via spin interactions but also by the Coulomb excitations, arising from the electrons localized by the oxygen vacancies. This approach of including Coulomb excitation in the modified carrier-mediated model could explain well the magnetic properties of ZnO:Co and solves the drawback of the carrier-mediated model in interpreting the appearance of ferromagnetism in the insulating ZnO:Co. We propose that the Coulomb excitations induced by the electrons captured by the oxygen vacancies are an essential element in the magnetic ZnO, which reveals the fact that the bound magnetic polaron model without considering the Coulomb excitation is insufficient to describe the magnetic properties of ZnO.

Prognostic significance of altered expression of SDC2 and CYR61 in esophageal squamous cell carcinoma.

The transforming growth factor beta (TGF-beta) signaling pathway plays an important role in growth and development, and is critically involved in the genesis and development of tumors. Syndecan-2 (SDC2) and Cysteine-rich 61 (CYR61) are important genes in this pathway and SDC2 is known to be a significant upstream regulator of TGF-beta signaling. However, the roles of SDC2 and CYR61 in the development of esophageal squamous cell carcinoma (ESCC) remain unclear. In the present study, we investigated the relationship between SDC2 and CYR61 mRNA expression levels and disease prognosis in patients with ESCC. The mRNA expression of SDC2 and CYR61 was detected by quantitative real-time RT-PCR in 77 tissue specimens. Quantitative real-time RT-PCR showed that SDC2 and CYR61 mRNA expression levels were aberrant in ESCC tissue (P<0.01) and that SDC2 mRNA expression was significantly associated with tumor size (P=0.024) in ESCC. CYR61 mRNA expression was significantly associated with regional lymph node metastasis (P=0.034) and tumor size (P=0.03). A positive correlation between SDC2 and CYR61 (r=0.770; P<0.001) mRNA expression was observed. Moreover, we observed significant associations between altered expression of SDC2/CYR61 and regional lymph node metastasis (P=0.009) and TNM stages (P=0.033). Aberrant mRNA expression of CYR61 and SDC2/CYR61 (P=0.005 and P=0.026, respectively) were significantly associated with patient survival time. The multivariate Cox regression analysis showed that SDC2 and CYR61 were independent prognostic factors for survival. Our findings suggest that SDC2 may act as an a upstream regulator of the TGF-beta signaling pathway and regulate the expression of downstream target genes. Moreover, SDC2 and CYR61 expression affect the severity of cancer, and the survival of patients with ESCC. Importantly, we report that SDC2 and CYR61 are significant, independent prognostic factors for survival in ESCC. These findings may have implications for targeted therapies in patients with ESCC.

A simple and sensitive HPLC-ESI-MS/MS method for the determination of andrographolide in human plasma.

A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for the determination of andrographolide in human plasma was established. Dehydroandrographolide was used as the internal standard (I.S.). The plasma samples were deproteinized with methanol and separated on a Hanbon C(18) column with a mobile phase of methanol-water (70:30, v/v). HPLC-ESI-MS/MS was performed in the selected ion monitoring (SIM) mode using target ions at [M-H(2)O-H](-), m/z 331.1 for andrographolide and [M-H](-), m/z 331.1 for the I.S. Calibration curve was linear over the range of 1.0-150.0ng/mL. The chromatographic separation was achieved in less than 6.5min. The lower limits of quantification (LLOQ) was 1.0ng/mL. The intra and inter-run precisions were less than 6.95 and 7.22%, respectively. The method was successfully applied to determine the plasma concentrations of andrographolide in Chinese volunteers.

Accelerating ethylene polymerization using secondary metal ions in tetrahydrofuran.

We have prepared a new series of nickel phosphine phosphonate ester complexes that feature two metal-chelating polyethylene glycol (PEG) side arms. Metal binding and reactivity studies in polar solvents showed that they readily coordinate external cations, including alkali (Li+, Na+, K+), alkaline (Mg2+, Ca2+), transition (Sc3+, Co2+, Zn2+), post-transition (Ga3+), and lanthanide (La3+) metals. Although olefin polymerization reactions are typically performed in non-polar solvents, which cannot solubilize +2 and +3 metal cations, we discovered that our nickel catalysts could promote ethylene polymerization in neat tetrahydrofuran. This advance allowed us, for the first time, to systematically investigate the effects of a wide range of M+, M2+, and M3+ ions on the reactivity of nickel olefin polymerization catalysts. In ethylene homopolymerization, the addition of Co(OTf)2 to our nickel-PEG complexes provided the largest boost in activity (up to 11-fold, 2.7 × 106 g mol-1 h-1) compared to that in the absence of external salts. The catalyst enhancing effects of secondary metals were also observed in studies of ethylene and polar olefin (e.g., propyl vinyl ether, allyl butyl ether, methyl-10-undecenoate, and 5-acetoxy-1-pentene) copolymerization. Notably, combining either Co2+ or Zn2+ with our nickel complexes increased the rates of polymerization in the presence of propyl vinyl ether by about 5.0- and 2.4-fold, respectively. Although further studies are needed to elucidate the structural and mechanistic roles of the secondary metals, this work is an important advance toward the development of cation-switchable polymerization catalysts.

Exosomes derived from mesenchymal stem cells inhibit mitochondrial dysfunction-induced apoptosis of chondrocytes via p38, ERK, and Akt pathways.

Osteoarthritis (OA) is the most common chronic joint disease worldwide. Chondrocyte, as the only resident cell type in cartilage, its apoptosis is of pathogenetic significance in OA. Mesenchymal stem cell (MSC)-based-therapy has been proved effective in OA in animals and clinical studies. Nowadays, the regenerative potential of MSC-based therapy is mostly attributed to its paracrine secretion, in which exosomes may play an important role. In the present study, we aimed to find out the significance of MSC-derived exosomes (MSC-Exos) on the viability of chondrocytes under normal and inflammatory conditions. Bone marrow MSCs (BMSCs) and chondrocytes from rabbits were cultured in vitro. BMSC-Exos were isolated by an ultracentrifugation method. Transmission electron microscopy and Western blot were used to identify exosomes. The internalization of BMSC-Exos into chondrocytes was observed by fluorescent microscope. The viability and apoptosis of chondrocytes induced by IL-1ß were tested through MTT method, Hoechst33324 dying, and mitochondrial damage measurement. Phosphorylation of p38, ERK, and Akt were evaluated by Western blot. The results showed that BMSC-Exos were round-shaped. Co-culturing BMSC-Exos with chondrocytes could observe the uptake of BMSC-Exos by chondrocytes. The viability decreased, apoptosis occurred, and the mitochondrial membrane potential of chondrocytes changed a lot when IL-1ß were given, but all the changes were almost abolished when BMSC-Exos was added. Furthermore, the phosphorylation of p38 and ERK were inhibited, and phosphorylation of Akt was promoted by BMSC-Exos compared with IL-1ß group. The present study demonstrated that BMSC-Exos inhibited mitochondrial-induced apoptosis in response to IL-1ß, and p38, ERK, and Akt pathways were involved. BMSC-Exo might represent a novel cell-free therapeutic approach for the treatment of OA.

Bioequivalence and pharmacokinetic comparison of a single 200-mg dose of meclofenoxate hydrochloride capsule and tablet formulations in healthy Chinese adult male volunteers: a randomized sequence, open-label, two-period crossover study.

BACKGROUND: Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and children's enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published. OBJECTIVE: The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis). RESULTS: Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Pharmacokinetic and bioequivalence comparison of a single 100-mg dose of cefteram pivoxil powder suspension and tablet formulations: a randomized-sequence, open-label, two-period crossover study in healthy Chinese adult male volunteers.

BACKGROUND: Cefteram pivoxil (CFTM-PI) is an oral antibiotic available in powder suspension and tablet formulations indicated in China for the treatment of bacterial infections. Although these 2 formulations are marketed in China, published information regarding their pharmacokinetics and bioequivalence in the Chinese population is not available. OBJECTIVE: The aim of this study was to compare the pharmacokinetics and bioequivalence of the powder suspension (test) and tablet (reference) formulations of CFTM-PI 100 mg available in China. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 100-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Plasma was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to 6 hours (AUC(0-6)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were obtained at intervals over the 6-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of C(max) and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). RESULTS: Twenty-four Chinese male subjects (mean [range] age,24.2 [23-32] years;weight,64.3 [58-67] kg; height, 172 [167-185] cm) enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C(max), AUC(0-6;), and AUC(0-infinity) were 96.5 to 120.1, 95.7 to 110.2, and 96.2 to 110.4, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No AEs occurred or were reported during the study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 100-mg dose of the powder-suspension formulation was bioequivalent to a single 100-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Determination of tegaserod by LC-ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.

A simple, rapid and sensitive high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C18 column with a mobile phase of methanol: 5 mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05 ng/ml. The calibration curves were linear over the range 0.05-8.0 ng/ml (r=0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8h under room temperature (25 degrees C, three freeze-thaw cycles in 30 days and for 30 days under -70 degrees C). After administration of a single dose of tegaserod maleate 4 mg, 6 mg and 12 mg, respectively, the area under the plasma concentration versus time curve from time 0 h to 12 h (AUC0-12) were (2.89+/-0.88), (5.32+/-1.21) and (9.38+/-3.42) ng h/ml, respectively; peak plasma concentration (Cmax) were (1.25+/-0.53), (2.21+/-0.52) and (4.34+/-1.66) ng/ml, respectively; apparent volume of distribution (Vd/F) were (6630.5+/-2057.8), (7615.2+/-2242.8) and (7163.7+/-2057.2) l, respectively; clearance rate (CL/F) were (1851.4+/-496.9), (1596.2+/-378.5) and (1894.2+/-459.3) l/h, respectively; time to Cmax (Tmax) were (1.00+/-0.21), (1.05+/-0.28) and (1.04+/-0.16) h, respectively; and elimination half-life (t1/2) were (3.11+/-0.78), (3.93+/-0.92) and (3.47+/-0.53) h, respectively; MRT were (3.74+/-0.85), (4.04+/-0.56) and (3.28+/-0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6mg, b.i.d) were as follows: Cssmax, (2.72+/-0.61) ng/ml; Tmax, (1.10+/-0.25) h; Cssmin, (0.085+/-0.01) ng/ml; Cav, (0.54+/-0.12) ng/ml; DF, (4.84+/-0.86); AUCss, (6.53+/-1.5) ngh/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4 mg, 6 mg and 12 mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication.

Determination of betamethasone and betamethasone 17-monopropionate in human plasma by liquid chromatography-positive/negative electrospray ionization tandem mass spectrometry.

This study presents a high-performance liquid chromatography-positive/negative electrospray ionization tandem mass spectrometric (LC-ESI(+/-)-MS-MS) method for the determination of betamethasone (BOH) and betamethasone 17-monopropionate (B17P) in human plasma using beclomethasone dipropionate as the internal standard (I.S.). Both compounds were extracted from human plasma with ether-cyclohexane (4:1, v/v) and were separated by HPLC on a Hanbon Lichrospher C(18) column with a mobile phase of methanol-water (85:15, v/v) at a flow rate of 0.7ml/min. Calibration curves were linear over the range of 0.10-50ng/ml for BOH and 0.050-50ng/ml for B17P. The inter-run relative standard deviations were less than 14.4% for BOH and 12.3% for B17P. The intra-run relative standard deviations were less than 9.3% for BOH and 7.9% for B17P. The mean plasma extraction recovery for BOH and B17P were in the ranges of 82.7-85.9% and 83.6-85.3%, respectively. The method was successfully applied to study the pharmacokinetics of a new formulation of betamethasone phosphate/betamethasone dipropionate injection in healthy Chinese volunteers.