Journal of Chinese Pharmaceutical Sciences

HER-2/EGFR, the major targets for anti-metastasis effect of tetraarsenic oxide on SKBR3 breast cancer cells

Qiuyu Liu, Illju Bae, Linlin Qian, Zenglin Lian

2017, 26(2): 87-94. DOI: 10.5246/jcps.2017.02.007

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Breast cancer is one of the most common female malignant tumors in the world. Although many therapeutic methods for HER-2 positive breast cancer have been developed, the drug resistance and distant metastasis still remain. Tetraarsenic oxide (As₄O₆) has been demonstrated with an anticancer effect on squamous cell carcinoma and cervical cancer. However, there is no report about the relationship between As₄O₆ and HER-2 positive breast cancer. In the present study, we detected the inhibitory efficacy and mechanism of As₄O₆ on the migration and invasion of SKBR3 breast cancer cells using molecular biological methods. The wound-healing assay, matrigel migration assay, transwell invasion assay and cell adhesion assay were used to assess the migration, invasion and adhesion of SKBR3 cells intervened by As₄O₆. Meanwhile, the reverse transcription-PCR and western blotting were performed to investigate the mechanism of As₄O₆on the migration and invasion of SKBR3 breast cancer cells. The results demonstrated that As₄O₆could efficiently inhibit the migration and invasion of SKBR3 cells, the HER-2 positive breast cancer cells, and the adhesion of SKBR3 cells was decreased after As₄O₆treatment. The mechanism revealed that As₄O₆ anticancer efficacy was related to HER-2/EGFR pathways. As₄O₆exerted its inhibitory effects on migration and invasion in HER-2 positive breast cancer cells by regulating the factors (EGFR, HER-2, Akt, MMP-9) in HER2/ EGFR signaling pathway and other key molecules. In conclusion, the present study indicated that As₄O₆ inhibited the invasion and migration process of HER-2 positive breast cancer SKBR3 cells by negatively regulating the HER-2/EGFR-mediated signaling pathway. These data provided evidence that As₄O₆ might serve as potential anti-metastasis drug for clinical treatment of breast cancer.

Syntheses, characterization, and evaluation of novel non-carboxylic analogues of Gemfibrozil: a bioisosteric approach

Nidhi Kala, Anand Gaurav, Vertika Gautam

2017, 26(2): 95-105. DOI: 10.5246/jcps.2017.02.008

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Gemfibrozil is a widely used lipid modifying drug with well-established hypolipidemic and anti-atherosclerotic benefits;however, the presence of a carboxylic acid moiety in its structure is responsible for side effects in the gastrointestinal tract. The principle of bioisosterism was applied to design derivatives replacing the carboxylic acid group. The carboxylic acid group was replaced with bioisoteric groups, such as 1,2,4-triazole-3-thiol and hydroxamic acid. The derivatives were then synthesized, characterized, and evaluated in rats for reduced gastrointestinal irritation and hypolipidemic effects. Gemfibrozil was used as standard for comparison. The derivatives demonstrated less gastric irritation and retained hypolipidemic effects, however the hypolipidemic affects were significantly less than that of Gemfibrozil. The results of this study offers a direction for further research on the application of bioisosterism for the design of new derivatives of Gemfibrozil and other fibric acid derivatives.

HPLC-MS/MS quantification of the HIV-1 protease inhibitor saquinavir in mice plasma and brain

Gongwen Liang, Na Li, Liping Ma, Libo Zhao, Luwen Shi

2017, 26(2): 106-114. DOI: 10.5246/jcps.2017.02.009

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In the present study, a rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of saquinavir in mice plasma and brain was developed, validated, and applied to a preliminary screening study evaluating the effect of bioflavonoids on the brain distribution of saquinavir in mice. Saquinavir and the internal standard (ritonavir) were isolatedfrom plasma and homogenized brain tissue matrices using a liquid-liquid extraction procedure, and the chromatographic separationwas accomplished by using a reversed phase C₁₈column (150 mm×2.1 mm, 5.0 μm). The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization, and multiple reaction monitoring was employed to select both saquinavir and ritonavir in the positive ion mode. A linear dynamic range of 0.1-10 ng/mL for plasma samples was established and the lower limit of quantification was 0.1 ng/mL. The intra- and inter-day precision were 7.5%-12.1%, and the accuracies ranged from 90.5% to 107.2% for plasma. A linear dynamic range of 0.1-10 ng/g for brain samples was established and the lower limit of quantification was 0.1 ng/g. The intra- and inter-day precision were 7.3%-11.9%, and the accuracies ranged from 90.8% to 107.4% for brain tissue samples. This method was successfully applied a preliminary screen of 19 bioflavonoids on the brain distribution of saquinavir in mice, and biochanin A shows the strongest effect.

Distribution and pharmacokinetics of five Rhubarb anthraquinones in rabbits and rats

Ting Cui, Qixin Zhou, Dan Zhang, Xinhui Jiang

2017, 26(2): 115-123. DOI: 10.5246/jcps.2017.02.010

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The main active components of Rhubarb are anthraquinones (AQs), most of which are glycosides and others are free. The concentrations of AQs derivatives (rhein, aloe-emodin, emodin, chrysophanol and physcion) in plasma and homogenate were assayed with a high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters and distribution of Rhubarb AQs in rabbits or rats were studied after administrationof different formulas. Elimination of AQs was fit to a two-compartment model in rats and rabbits. There were no significant difference in the main pharmacokinetic parameters between rhein and AQs in rats. AQs were distributed progressively in the kidney, liver, blood, and heart. The AQs were mainly composed of rhein in vivo and was excreted by the kidney. For formulas that contained Rhubarb, rhein could be used as a probe for in vivo pharmacokinetic studies.

Determination of diethylstilbestrol in human plasma using high performance liquid chromatography-tandem mass spectrometry

Zhaohui Qiu, Xiang Xie, Peigen Zhou, Peng Yu, Feng Gao

2017, 26(2): 124-129. DOI: 10.5246/jcps.2017.02.011

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A sensitive, fast, and reproducible high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of diethylstilbestrol in human plasma was developed and validated. The plasma samples were pretreated by direct deproteinization with ethyl acetate. Daidzein was used as the internal standard. The separation was carried out on a Agilent Technologies 1200 series XDB C₁₈ column (2.1 mm×150 mm, 5 µm) with a mobile phase of acetonitrile-2.5 mmol/L ammonium acetate (60:40, v/v). Triple quadrupole mass spectrometric detection in negative ion mode was used for multiple-reaction-monitoring of the transitions atm/z 267.2→237.3 and m/z 253.2→132.3 for diethylstilbestrol and daidzein, respectively.The calibration curves were linear over the concentration range from 0.1 to 20 ng/mL (r²= 0.9984). The lower limit of quantificationwas 0.1 ng/mL (s/n mLs)for diethylstilbestrol, which was sensitive enough to perform pharmacokinetic studies after diethylstilbestroladministration. Inter-day and intra-day precisions were no more than 7% with accuracies of 90%-105%. This method could be applied to therapeutic drug monitoring of diethylstilbestrol, which is helpful for evaluating the clinical efficacy and safety of diethylstilbestrol.

Optimization of ultrasound assisted extraction of celastrol from Celastrus monospermus Roxb. using response surface methodology

Chaohai Pang, Gong Fang, Dingyong Wang

2017, 26(2): 130-138. DOI: 10.5246/jcps.2017.02.012

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In the present study, we aimed to investigate the effects of key extraction parameters including extraction time (10-20 min),extraction temperature (30-60 °C), ultrasonic power (60-90 W) and solvent-to-solid (S/S) ratio (10-30 mL/g) on yield of celastrol from Celastrus monospermus Roxb. To optimize the conditions, we investigated the effects of parameters on the ultrasound assisted extraction (UAE) with the Box-Behnken Design (BBD), one widely used form of Response Surface Methodology (RSM). In all tested solvents, ethanol was the most effective for celastrol extraction, followed by methanol, ethanol, ethyl acetate, n-butanol and water. A second order polynomial model was fitted well to the extraction experimental data with R² of 0.9928. Extraction yield of 3.116 mg/g was obtained for celastrol under the optimized extraction conditions of extraction time (20 min), extraction temperature (46 °C), ultrasonic power (60 W) and S/S ratio (30 mL/g). Experimental validation was performed, and the experimental values agreed well with the predicted values. The results indicated that the UAE was good extraction material for celastrol from C. monospermus Roxb.

Analyzing the risk of drug abuse for morphine-containing Chinese patent medicines in China

Jieying Lin, Jingjing Liu, Yaning Qi, Chunming Wang

2017, 26(2): 139-146. DOI: 10.5246/jcps.2017.02.013

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Chinese patent medicines (CPMs) are widely used across China, and they are differently administrated from chemical drugs. For traditional reasons, CPMs may contain opium-derived compounds, such as morphine, which may pose the issues of drug abuse and addiction. In the present study, we aimed to evaluate the present risk of morphine-containing CPMs in causing drug abuse and addiction, based on a questionnaire-based approach and from a medicinal administrative perspective. We chose 76 CPMs containing morphine from government document and set them as the study group, and 10 chemical drugs containing morphine were set as the control group. Because there is no ready-made method, we created an evaluation sheet consisting of five questions to evaluate each drug and generate a risk-value score. Crosstabs analysis using SPSS 15.0 was conducted to obtain the influencing factors. We found that the study group obtained a mean score of 2.04 for the risk value, which was five times of that of the control group. Specifically, no maximum limit of morphine or codeine was set in product quality standards for more than four-fifth of the drugs. Moreover, 46.0% of package inserts failed to show any warning about addiction or prohibition over the long-term use of the drugs. The number of ingredients, as well as the functions of the drugs, was found to correlate with the risk value. Our findings suggested that CPMs were more risky in causing drug abuse and addiction than chemical drugs. Approaches, such as i) controlling the number of ingredients, ii) setting up maximum limit of morphine or codeine in quality standard, iii) providing more information on the package insert of drugs and iv) monitoring the drug containing both morphine and ephedrine, will be effective in reducing the risk of drug abuse and addiction.

Chronic disease and its therapeutic drugs may effect on the postoperative 5-year survival rate of lung cancer patients

Liang Shi, Zeng Wang, Tingting Yu, Liang Xia

2017, 26(2): 147-155. DOI: 10.5246/jcps.2017.02.014

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In this study, we aimed to investigate the influencing factors of postoperative 5-year survival rate in non small-cell lung cancer (NSCLC) patients with stage I-III. We enrolled 220 patients who underwentsurgical operation and survived longer than 3 months, with histologically confirmed adenocarcinoma or squamous cell carcinoma from Jan. 2009 to Dec. 2009. Multiple variables, like age, gender, smoking, alcohol, obesity, family history of cancer, diabetes, hypertension, antidiabetic drugs, tumor staging, pathology, treatments, surgical side as well as lipid levels, were selected. We found that tumor staging was associated with 5-year survival rate of stage I-III NSCLC patients by univariate analysis. Furthermore, diabetes mellitus, hypertension andsurgical side were associated with the overall survival of NSCLC patients with stage I, stageⅡand stageIII, respectively. In conclusion, the status of chronic disease had potential effect on the postoperative 5-year survival rate of lung cancer patients.

Chemical constituents isolated from the endophytic fungus Penicillium commune

Xintao Chen, Hong Lan, Tao Zheng, Yongcheng Dong, Jun Liang, Chen Li

2017, 26(2): 156-160. DOI: 10.5246/jcps.2017.02.015

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Phytochemical investigation of the endophytic fungus Penicillium communeled to the isolation of nine known compounds.Based on the spectroscopic and chemical properties, their structures were identified as 6-acetyl-2α,5-dihydroxy-2-(2-hydroxypropyl)-3α,8-dimethylchroman (1), communol B (2), communol E (3), communol G (4), 2-hydroxy-4-phenylquinoline (5), viridicatol (6), 3-O-methylviridicatin (7), trans-ferulic acid (8), 1,2-benzenediol,4-(2-methoxyethenyl) (9). Compounds 1 and 5-9 were isolated from this fungus for the first time.

A Review of CDER’s Novel Drug Approvals for 2016

John Jenkins M.D.

2017, 26(2): 161-162.

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