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Table of Content

    19 July 2016, Volume 25 Issue 7
    Cancer prevention by traditional Chinese medicine and plant phytochemicals column
    Development and validation of a rapid UPLC/MS method for the simultaneous determination of I3C, DIM, and related metabolites and its application to pharmacokinetics studies
    Yury Gomez, Hu Wang, Ah-Ng Tony Kong
    2016, 25(7):  477-488.  DOI: 10.5246/jcps.2016.07.053
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    Indole-3-carbinol (I3C) and diindolylmethane (DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-performance liquid chromatography(UPLC) coupled with mass spectrometry (MS), a rapid, specific, and high throughput method was developed and validated for the quantification and identification of I3C, DIM, and other I3C metabolites in plasma. Samples containing I3C or DIM and the internal standard 4-methoxy indole (IS) were extracted using a liquid-liquid extraction technique. The mean recovery was 96.21% for I3C and 108.5% for DIM. Separation was achieved using a Waters Acquity UPLC HSS T3, 1.8 µm, 2.1 mm×150 mm column and acetonitrile–water gradient elution. The flow rate was 0.3 mL/min and the run time was 9 min. The limits of detection and quantification for I3C and DIM were 15 ng/mL and 25 ng/mL, respectively. Calibration curves for I3C and DIM were linear (r2>0.99) over a concentration range of 0.025–20 µg/mL. Precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters of I3C or DIM after oral, intravenous, or intraperitoneal administration to Sprague Dawley rats. The method described here is superior over existing analytical methods for I3C and its metabolites in terms of sensitivity, speed, and separation.

    Original articles
    Efficacy and mechanism of antiresistant vinorelbine liposomes in treating resistant breast cancer cells
    Hongjun Xie, Lei Liu, Fan Zeng, Limin Mu, Yao Zhao, Yan Yan, Yingjie Hu, Jiashuan Wu, Yingzi Bu, Jingying Zhang, Wanliang Lu
    2016, 25(7):  489-501.  DOI: 10.5246/jcps.2016.07.054
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    Among the comprehensive treatment strategies of breast cancer, chemotherapy plays a crucial role in eliminating cancer cells. However, multidrug resistance is one of the major obstacles to successful treatment. The objectives of this study were to construct an antiresistant vinorelbine liposomes and to demonstrate the efficacy and mechanism for treating resistant breast cancer cells. The study was performed using breast cancer MCF-7/adr cells. The antiresistant vinorelbine liposomes were modified with tamoxifen and dequalinium. The average particle size of antiresistant vinorelbine liposomes were approximately 100 nm, and they showed a robust overall anticancer efficacy by direct killing and by apoptosis induction. The mechanisms were associated with increased cellular uptake, decreased ABCB1 and ABCC10 transporters, and targeting to mitochondria. The apoptosis signaling pathways were ralated to activiated caspases (8, 9, 3), induced release of cytochrome c from mitochondria, activated Bax, inhibited Mcl-1, and generation of ROS. The new antiresistant vinorelbine liposomes could be a useful formulation deserving further development, and the present study provides a potential strategy for circumventing drug resistance in breast cancer.

    Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft
    Ming Hua, Xiwei Ji, Runtao Li, Shuangmin Ji, Jian Li, Qingyu Yao, Lijie Wang, Fangran Hao, Wei Lu, Tianyan Zhou
    2016, 25(7):  502-511.  DOI: 10.5246/jcps.2016.07.055
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    In the present study, we aimed to investigate the anticancer effect of TM208 (4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride) on non-small cell lung cancer (NSCLC). Moreover, pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and simulate the time-course of the drug response in A549 xenograft model. The inhibition rates of two treatment groups (TM208 100 mg/kg group and TM208 150 mg/kg group) in A549 xenograft model were first compared with both vehicle and positive control groups. Subsequently, natural tumor growth model was built and finally PK-PD model was established based on the PD data of the vehicle control group and TM208 treatment groups. In addition, the model was further evaluated, and the anti-cancer efficacy under different regimens was simulated. Our results showed that NSCLC was one potential indication of TM208 and TM208 150 mg/kg QD would be an effective regimen. For parameters about tumor growth, the initial volume was 0.134 cm3 and the growth rate was 0.0869 day1. For parameters about drug efficacy, the killing factor was 0.174 mL/μg/dand average transit rate among transit compartments was 0.173 day1. Among various regimens in the step of simulation, TM208 900 mg/kg QW, which was a hypothetical regimen without experimental data support yet, showed similar anticancer effect compared with TM208 150 mg/kg QD. In conclusion, the anti-cancer effect of TM208 on NSCLC was demonstrated by the pre-clinical experiment and confirmed by the developed PK-PD model. Moreoever, results from model simulation would be helpful for further translational research of TM208.

    Pharmacokinetically determined docetaxel exposure as a predictor of hematologic toxicity in Chinese patients with early stage breast cancer
    Fang Wang, Zhuo Chen, Lin Li, Mingzhi Zhu, Youyi Xiong, Yuanting Gu
    2016, 25(7):  512-516.  DOI: 10.5246/jcps.2016.07.056
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    Neutropenia is the major dose-limiting toxicity in patients being treated with docetaxel. The purpose of this study was to evaluate the relationship between pharmacokinetically determined docetaxel exposures and grade 34 hematologic toxicity (neutropenia and leukopenia) in Chinese breast cancer patients.Patients received docetaxel infusions (75 mg/m2 over 1 h) once every 3 weeks. At the first cycle, a patient’s docetaxel exposure was determined as an area under the curve (AUC) using plasma concentrations of docetaxel measured at two different time points (at the end of the infusion and 30–60 min later). Pharmacokinetic studies and toxicity assessments were performed for 61 patients. Grade 34 neutropenia occurred in 34 (55.7%) patients, and grade 34 leukopenia occurred in 30 (49.2%) patients. Individual exposure to docetaxel was highly variable (AUC range = 1.06.2 mg·h/L, inter-individual CV = 39.6%). There was a significant difference in the mean docetaxel AUC by grade of toxicity for both neutropenia and leukopenia. The average AUC for low (0–2) and high grade (3–4) neutropenia was 2.0 and 2.8 mg·h/L, respectively (P = 0.001), and for leukopenia was 1.9 and 2.9 mg·h/L, respectively (P<0.0001). Individual exposure to docetaxel is variable and predictive of high grade hematologic toxicity. The optimal docetaxel AUC to maximize efficacy and minimize toxicity in Chinese breast cancer patients merits further investigation.

    Pharmacokinetic characterization of a novel α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator LD486 in rat plasma using a validated LC-MS/MS assay
    Xiaomin Huang, Wenxuan Jiao, Qi Sun, Kewei Wang
    2016, 25(7):  517-525.  DOI: 10.5246/jcps.2016.07.057
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    The deficiency of neuronal α7-nicotinic acetylcholine receptor (α7 nAChR) channel is implicated in cognition deficit and neuropsychiatric disorders. Chemical activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR activators, we recently identified a lead compound LD486 that as a positive allosteric modulator (PAM) selectively activates α7 nAChR. In this study we developed a simple, reliable and efficient assay of high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed the pharmacokinetics of this novel LD486 in rat plasma. Separation of compound LD486 from plasma was achieved using a reversed-phase C18 column with a mobile phase of 0.1% formic acid in H2O (80:20, v:v), using compound A1223 as an internal standard (IS) with a flow rate of 0.5 mL/min. The quantitative analysis was performed using multiple reaction monitoring (MRM) at the specific ion transition of m/z 419.0 [M+H]+m/z 169.0 for LD486 and m/z 400.0 [M+H]+m/z 129.9 for A1223 in the positive ion mode with electrospray ionization (ESI) source. This validated LC-MS/MS method shows good linearity over the range 4–4000 ng/mL with the lowest limit of quantitation (LLOQ) at 4 ng/mL as well as satisfied intra- and inter-day precision, accuracy, extraction recovery and matrix effect.The stability testing indicates that LD486 in rat blood is stable under three freeze-thaw cycles, in room temperature at 22 oC for 2 h and 12 h, and for 2 weeks at −20 oC. This developed method was successfully applied to the pharmacokinetic analysis of intravenous (1 mg/kg) and oral (3 mg/kg and 30 mg/kg) administration of LD486 in SD rats.

    Quantification of tulobuterol, a selective β2 adrenergic agonist, in human plasma by liquid chromatography-tandem quadrupole mass spectrometry
    Longmei Cheng, Guangtao Hao, Xueyi Chen, Yingfu Zhang, Yuanyuan Zhang, Ruihua Dong, Zeyuan Liu, Hengyan Qu
    2016, 25(7):  526-534.  DOI: 10.5246/jcps.2016.07.058
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    A simple and highly sensitive method coupled with liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS) was developed and validated for the determination of tulobuterol in human plasma. Sample was preparated by liquid-liquid extraction with i-propanoln-hexane (5:95, v/v). Tulobuterol and tulobuterol-d9 (internal standard, IS) were separatedon a 300 Extend C18 column(4.6 mm×150 mm, 5 µm), using 0.1%formic acid (A)acetonitrile (B) (30:70, v/v) as the mobile phase at the flow rate of 1.0 mL/min with an approximately 1:1 split entering the mass spectrometer. Detection was performed by positive electrospray ionization mass spectrometry multiple reaction monitoring of the precursor-to-product ion transition of tulobuterol at m/z 228.1→m/z 154.0 and tulobuterol-d9 atm/z 237.2→m/z 154.0. The assay was linear over the range 0.015.0 ng/mLwith a lower limit of quantitation of 0.01 ng/mL. The intra- and inter-day precisions were 3.7% and 11.1%, respectively. Recoverywas approximately 66%, and matrix effects were minimal. This method also showed satisfactory sensitivity, specificity, and carryover. The method was successfully applied to a pharmacokinetic study of tulobuterol in healthy volunteers who were given the tulobuterol patch containing 2 mg tulobuterol.

    Comparison of effects on bone mesenchymal stem cells differentiation between lanthanum and gadolinium under high phosphate condition
    Caixia Yu, Jiao Gong, Jian Huang, Tianlan Zhang, Kui Wang
    2016, 25(7):  535-545.  DOI: 10.5246/jcps.2016.07.059
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    Lanthanum (La) and gadolinium (Gd) have been used in clinical diagnosis and treatment. The application of La and Gd in medication may cause accumulation of the elements in bone. Whether the similar physicochemical properties of these two Lanthanides (Lns) will lead to similar biological effects on bone metabolism in patients with severe kidney failureare key concerns of researchers.This study compared the influences of LaCl3 and GdCl3 on in vitro differentiation of bone mesenchymal stem cells (BMSCs) in high phosphate (Pi) medium. The results showed that LaCl3 inhibited high Pi-induced BMSC differentiation at higher concentration and stimulated BMSC differentiation-related genes at lower concentration, while GdCl3 promoted high Pi-induced BMSC differentiation. The emergence of insoluble Ln-containing calcium phosphate (CaP) was implicated in the process of LaCl3 or GdCl3 mediated osteogenic differentiation.The small differences in atomic number of La and Gd causedthe more promotive effect of GdCl3on the precipitation of CaP compared with LaCl3.Moreover, the content of serum proteins coprecipitated in Gd-containing particles was decreased compared with La-containing particles, leading to larger particle size of Gd-containing particles.The study demonstrated that those distinct physicochemical propertiesof Gd-containing particlesvs. La-containing particlesplayed an important role in modulatingthe different effects of GdCl3and LaCl3on BMSC differentiation.

    Preventive effect of Peperomia pellucida (L.) Kunth herbs on ovariectomy-induced osteoporotic rats
    Cynthia Astiti Putri, I Gusti Agung Ayu Kartika, I Ketut Adnyana
    2016, 25(7):  546-551.  DOI: 10.5246/jcps.2016.07.060
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    Osteoporosis is a metabolic skeletal disorder leading to bone fracture which adversely impacts the quality of life. In the present, we aimed to investigate the effect of Peperomia pellucida (L.) Kunth herb juice and ethanolic extract on ovariectomy (OVX)-induced osteoporotic rat model. Osteoporosis was induced by OVX with a double dorsolateral approach on female Wistar rats. Female Wistar rats undergoing sham surgeries (sham-control group) served as controls. The ovariectomized rats were divided into six groups based on administered treatments, (i) CMC Na 0.3% (OVX-control group), (ii) standard drug (ethynil estradiol 4.5 µg/kg), (iii) P. pellucida juice at dose of 50 mg/kg, and (iv) 100 mg/kg, (v) P. pellucida ethanolic extract at dose of 50 mg/kg, and (vi) 100 mg/kg. Treatments were started 1 week after the surgeries and lasted for 6 weeks. Rats treated with 100 mg/kgP. pellucida ethanol extract had significantly decreased serum ALP level and reduced excretion of urine calcium compared with the OVX-control group (P<0.05). These levels were not significantly altered when compared with the sham-control group (P<0.05). Furthermore, 100 mg/kg ethanolic extract-treated group showed improvement on three-dimensional image of the trabecular bone compared with the OVX-control group. Trabecular cavity formation in 100 mg/kg ethanolic extract-treated group was minimal. Ethanolic extract of Peperomia pellucida (L.) Kunthherbs at a dose of 100 mg/kg had preventive effect on OVX-induced osteoporotic rats.

    Drug administration column
    Implementation strategy for eCTD electronic submission in China based on experiences from ICH countries
    Xiaolin Zhu, Bin Li, Dongsheng Yang, Bin Jiang
    2016, 25(7):  552-558.  DOI: 10.5246/jcps.2016.07.061
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    With the development of information technology and pharmaceutical science, eCTD (electronic common technical document) has gradually become the main format for pharmaceutical registration dossiers all over the world, especially the ICH (the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) countries. In 2015, CFDA (China Food and Drug Administration) emphasized the significance of establishing a uniform specification for registration applications, extensively applying CTD format in China and enforcing eCTD electronic submissions step by step. In this study, we summarized the international experiences on implementation of eCTD from ICH countries and analyzed China’s current regulatory status. A survey was carried out to investigate the feasibility of implementing eCTD electronic submission in China, the possible problems to be faced with and the related solutions. Finally, recommendation on eCTD implementation strategy in China was proposed.