Table of Content

26 April 2017, Volume 26 Issue 4

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Original articles

Berberine enhances Ucp1 expression via modulating the NFE2 response element in cold environments: new perspectives on the thermogenesis in brown adipose tissue

Xi Lu, Zhiyi Yuan, Jingfei Jiang, Fan Lei, Tianshi Feng, Yugang Wang, Xinpei Wang, Dongming Xing, Jun Li, Lijun Du

2017, 26(4):  237-254.  DOI: 10.5246/jcps.2017.04.025

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Berberine (BBR) has a variety of pharmacological activities. Studies have reported that BBR not only reduces heat stress-induced fever but also inhibits lower body temperatures due to cold stress. Heat stress can be reduced via BBR treatment, which antagonizes HSP70-TNFα to regulate the body temperature alteration. In cold stress, however, the molecular mechanism of BBR-induced inhibition of hypothermia remains unclear. Therefore, we studied whether BBR promoted uncoupling protein1 (UCP1, a crucial protein of thermogenesis) expression and its mechanism under cold stress. Wild type mice and Ucp1^–/– mice were used for the in vivo experiments, and primary brown adipocytes and brown adipocytes HIB-1B were used for the in vitrostudies. The cold stress was set at 4 °C. The results showed that at 4 °C, the body temperature of mice was decreased. BBR effectively inhibited this hypothermia. Simultaneously, Ucp1 expression in brown adipose tissue (BAT) cells was significantly increased, and BBR promoted Ucp1 expression. However, in Ucp1-knockout mice, the effect of BBR on hypothermia disappeared during cold stress, indicating that the main target for BBR regulation of body temperature was Ucp1. Further studies showed that the transcriptional response element NFE2 (nuclear factor erythroid-derived 2) in the upstream of theUcp1 promoter region contributedto the positive regulatory role on Ucp1 expression at lower temperature. BBR could bind to the sequence of NFE2 response element in a temperature-dependent manner. Increased affinity of BBR binding to NFE2 response element in cold stress significantly strengthened and enhanced the expression of Ucp1. This work was important for understanding the role of BBR on thermogenesis in BAT, body temperature regulation and temperature tolerance under cold conditions.



A novel type of functional epirubicin liposomes modified with DSPE-PEG2000-cyclopamine conjugate for eliminating heterogeneous breast cancer cells

Yingjie Hu, Jingying Zhang, Lei Liu, Yan Yan, Limin Mu, Jing Bai, Jiashuan Wu, Wanliang Lu

2017, 26(4):  255-264.  DOI: 10.5246/jcps.2017.04.026

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Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells (such as cancer stem-likecells), resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog (Hh) signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of functional drug liposomes for eliminating heterogeneous cancer. The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol (DSPE-PEG₂₀₀₀)-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epirubicin liposomes were successful constructed by modifyingwith DSPE-PEG₂₀₀₀-cyclopamine, displaying a particle size in nano-scale (approximately 98 nm) and a high epirubicin encapsulation (>97%). The CD44+/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, functional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.



Preparation and stability studies of dimethyl curcumin niosomes

Rui Li, Defeng Xu, Xingqun Yang, Shouxiu Ma, Xiaoai Ge, Shuwen Zhou

2017, 26(4):  265-270.  DOI: 10.5246/jcps.2017.04.027

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In the present work, we aimed to optimize the preparation technology of dimethyl curcumin niosomes, improve its solubility and assess its stability. The novel anti-androgen dimethyl curcuminniosomes were prepared by thin-film dispersion-ultrasonic method, and the prescription composition and preparation process were optimized by single-factor investigation method. Certainly, the solubility and quality evaluation of dimethyl curcumin niosomes were also investigated. The average particle size of prepared dimethyl curcumin niosomes was (310.3±0.9) nm. The highest encapsulation rate was 88.1%±1.7%, and the drug-loading amount was 4.03%±1.05%. Moreover, the leakage rate was below 2% within 45 d. Collectively, all these findings indicated that the niosomes, as a vector, could significantly improve the solubility and stability of dimethyl curcumin, offering a theoretical basis for dimethyl curcumin as an anticancer drug in medicine application.



Development and validation of a novel UPLC-MS/MS method for the simultaneous determination of fluticasone propionate and salmeterol in human plasma

Yuxiong Gao, Li Ding, Wenzhong Liang, Huafang Jiang

2017, 26(4):  271-283.  DOI: 10.5246/jcps.2017.04.028

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Combined administration of fluticasone propionate and salmeterol xinofoatehas been widely used for the treatment of asthma in recent decades. In this investigation, we developed and validated a novel and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of fluticasone propionate and salmeterol xinofoate in human plasma. Following a simple SPE sample extraction in 96-well plate format, chromatography was performed on a Waters ACQUITY UPLC BEH C₁₈ column (1.7 μm, 50 mm×2.1 mm) with mobile phase consisting of 100% MeOH and 0.1% NH₄OH in water on a gradient program at flow rate of 0.5 mL/min. Detection of analytes and internal standards was accomplished using multiple reaction monitoring (MRM) of precursor>product ion pairs of m/z 501.4>313.2(fluticasone propionate), 506.4>293.3 (fluticasone propionate-d5), 416.4>232.1 (salmeterol xinofoate) and 419.3>235.2 (salmeterol-d3). The assay range was 2.50–500 pg/mL for both analytes, and a 1/x² weighted linear regression model was used. The inter-assay accuracy and precision of the method were within ±8.6%. The recoveries from 0.30 mL of plasma were greater than 51.0% and 54.6% for fluticasone propionate and salmeterol, respectively, and the results were consistent across low, middle and high concentration levels. The method was validated following FDA, EMA and CFDA (China Food and Drug Administration)’s guidance on bioanalysis and then successfully applied to support a clinical study in healthy Chinese subjects following inhaled administration of a single combination of fluticasone propionate/salmeterol (250 μg/50 μg).



Bioavailability and pharmacokinetics of alantolactone from Inula helenium in rats following intravenous and oral administrations

Xinguo Zhang, Jinweng Liu, Fei Kou, Qianglin Wang, Ziyu Liu, Jianyong Li

2017, 26(4):  284-290.  DOI: 10.5246/jcps.2017.04.029

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Alantolactone, as the principal constituent of Inula Helenium L, has been shown various pharmacologic activities, such as anti-inflammatory and deworming. In the present study, we developed a high performance liquid chromatography (HPLC) method for the determination of alantolactone in rat plasma, and pharmacokinetics of alantolactone was investigated after intravenous and oral administrations to Wistar rats. Separation was achieved on C₁₈ column (4.6 mm×250 mm, 5.0 μm) using a mobile phase consisting of methanol–water (70:30, v/v) at a flow rate of 1.0 mL/min. The wavelength of the ultraviolet detector was set at 239 nm. The excellent linearity was found over a concentration range of 0.08–10 μg/mL (R² = 0.9998).The intra- and inter-day precisions were good, and the RSD was lower than 2.27%. The mean absolute recovery of alantolactone in plasma ranged from 88.09% to 95.57%. After intravenous administration, alantolactone showed rapid systemic clearance (CL (0.11±0.014) L/h/kg) and small volume of distribution (Vd (0.71±0.14) L/kg). The biological half life (t_1/2) was 56.24 min. After oral administration, alantolactone showed rapid oral absorption in rats, with a short T_max of(45.02±0.88) and (45.13±0.39) min for 14 and 28 mg/kg, respectively.The bioavailability of alantolactone in rats was 50.88%, indicating that alantolactone was orally available.



Pharmacokinetics and bioequivalence analysis of amlodipine tablets in Chinese female and male volunteers by HPLC-MS/MS

Sisi Cao, Yang Deng, Hualin Cai, Zhenyan Hou, Miao Yan, Bikui Zhang

2017, 26(4):  291-297.  DOI: 10.5246/jcps.2017.04.030

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In the present study, we determined the pharmacokinetics and bioequivalence of two amlodipine tablets in Chinese male and female volunteers using HPLC-MS/MS method. A randomized, two-period and crossover design was conducted in 20 healthy volunteers (14 male subjects and six female subjects). A single dose of either the reference or test formulation was given at the start of each period. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 and 144 h after drug administration. Plasma amlodipine was detected by HPLC-MS/MS method, and the pharmacokinetic parameters were analyzed using DAS 3.2.8. The developed HPLC-MS/MS method was suitable for the analysis of amlodipine in biological matrix samples. The main pharmacokinetic parameters between the trial preparation and the reference preparation met the regulatory criteria for bioequivalence, and the two preparations were both well tolerated.



Quality standard study on Dictamni Cortex

Ling Wang, Mingbo Zhao, Yong Jiang, Pengfei Tu, Xiaoyu Guo

2017, 26(4):  298-303.  DOI: 10.5246/jcps.2017.04.031

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Asa traditional Chinese medicine (TCM), Dictamni Cortex is widely used for the treatment of rheumatism and skin diseases. To promote the internationalization of Dictamni Cortex, we established a recommended quality standard of Dictamni Cortex according to the European Pharmacopoeia (EP) in the present study. Foreign matter, loss on drying, total ash and ash insoluble in hydrochloric acid were determined according to the procedures of EP 8.0. The thin layer chromatography (TLC) identification method was established by using obacunone and fraxinellone as the reference substances. The content of dictamnine, obacunone and fraxinellone was assayed by reversed phase high performance liquid chromatography (RP-HPLC). Furthermore, we tested 21 batches of the prepared slices of Dictamni Cortex from different regions. The results indicated that the established quality standard was specific, accurate and internationalized, which could be used for the quality control of Dictamni Cortex.



Simultaneous determination of seven bioactive constituents in Liuwei Wuling tablet by HPLC coupled with DAD

Ling Cheng, Xiaohan Wang, Baode Shen, Pinghua Xu, Chengying Sheng, Juan Zheng, Weibo Liao, Rong Xu, Hailong Yuan

2017, 26(4):  304-311.  DOI: 10.5246/jcps.2017.04.032

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We employed high performance liquid chromatography (HPLC) method coupled with diode array detector (DAD) for the determinationof seven major bioactive compounds (forsythoside A, specnuezhenide, phillyrin, schisandrin, schisantherin A, deoxyschizandrin and schisandrin B) in Liuwei Wuling tablet (LWWLT). The HPLC baseline separation was carried out on an Inertsil^® ODS-3 column (250 mm×4.6 mm, 5 μm) at 25 °C with a gradient elution system composed of 0.1% phosphoric acid solution and acetonitrile. The detection wavelength was set at 230 nm. Calibration curves for seven compounds showed good linear regressions, with correlation coefficients exceeding 0.999 within the tested concentration range. The limits of detection and quantification of each compound were in the range of 0.03–0.28 μg/mL and 0.11–0.87 μg/mL, respectively. The relative standard deviation values of precision, stability and repeatability were less than 2.34%. The average recovery of all seven constituents ranged from 96.71% to 103.9%. The validated quantification method was successfully applied for the analysis of 10 batches of commercial LWWLT from Shandong Shibo Jindu Pharmaceutical Co., Ltd. These results would make foundations for quality control and the further pharmacology study of LWWLT.



Drug administration column

Pharmacy intervention of irrational medical orders on pharmacy intravenous admixture services of outpatient and emergency departments in Fujian Provincial Hospital

Hongjin Gao, Shaoming Wang, Jie Zhuang, Yuxing Chen, Cheng Mi

2017, 26(4):  312-316.  DOI: 10.5246/jcps.2017.04.033

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In the present study, we aimed to analyze the irrational medical orders and evaluate the effect of pharmacy intervention on pharmacy intravenous admixture services of outpatient and emergency departments in our hospital. The irrational medical orders of PIVAS at the outpatient and emergency departments were retrospectively analyzed in Jun. 2015. We strengthened the pharmacy intervention on irrational medical orders since July 2015. All the cases were selected by systematic sampling method. Cased studied in Jun. 2015 served as the control group, whereas those studied in Jan. 2016 served as the intervention group. The irrational rate and the irrational number of daily average were compared between the control group and intervention group.The common type of irrational outpatient and emergency intravenous orders mainly included irrational use of solvents, irrational dosing interval and inappropriate compatibility of drugs. The irrational rate was reduced from 17.4% to 3.3% (P<0.01), and the irrational number of daily average was decreased from 5.23 to 1.00 (P<0.01).Pharmacy intervention can reduce the irrational rate of medical orders in our hospital, which is of great significance to promote rational drug use and improve medical quality.