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Welcome to Chinese Journal of Clinical Pharmacology and Therapeutics,Today is Chinese

Table of Content

    Volume 26 Issue 4
    26 April 2021
    Tetramethylpyrazine attenuates doxorubicin induced cardiotoxicity through 14-3-3γ/Bcl-2
    DING Xueming, CHEN Tianpeng, XU Qiang, HE Huan, HE Ming
    2021, 26(4):  361-367.  doi:10.12092/j.issn.1009-2501.2021.04.001
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    AIM: To investigate the effect of tetramethylpyrazine (TMP) on doxorubicin (Dox) induced cardiotoxicity and the role of 14-3-3γ/Bcl-2 protein expression. METHODS: Primary cultured cardiomyocytes were randomly divided into Control group, Dox group, Dox+TMP group and Dox+TMP+pAD/14-3-3γ-shRNA group. After 48 hours, the cell viability was detected by MST, the activity of LDH in culture medium, the activities of Caspase-3, SOD, GSH-Px and the content of MDA were detected; the expression of 14-3-3γ and mitochondrial Bcl-2 was detected by Western blot; ROS generation, mitochondrial membrane potential and mPTP opening were detected by flow cytometry; apoptosis was detected by TUNEL method. RESULTS: After Dox exposed for 48 hours, the viability of cardiomyocytes decreased significantly, the activity of LDH in culture medium increased, the activities of SOD and GSH-Px decreased, the content of MDA increased, ROS generation increased; the mitochondrial membrane potential decreased, mPTP continued to open, caspase-3 activity and apoptosis increased. TMP pretreatment significantly upregulated the expression of 14-3-3γ and mitochondrial Bcl-2, and reversed the above changes simultaneously; pAD/14-3-3γ-shRNA not only downregulated the expression of 14-3-3γ, but also decreased the expression of Bcl-2 in mitochondria. CONCLUSION: TMP pretreatment upregulates the expression of 14-3-3γ and mitochondrial Bcl-2, inhibits oxidative stress, maintains mitochondrial function and reduces Dox induced apoptosis.
    Reversal effects and mechanisms of Flavonoids from Tetrastigma hemsleyanum on drug resistance in gefitinib-resistant lung cancer cells
    HE Jiaqi, LI Juanjuan, LV Xiaoai, ZHANG Huanhuan, YU Chenhuan
    2021, 26(4):  368-375.  doi:10.12092/j.issn.1009-2501.2021.04.002
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    AIM: To investigate the sensitization of flavonoids from Tetrastigma hemsleyanum (FTH) on gefitinib (GEF)-resistant lung adenocarcinoma cells.  METHODS: The viabilities of A549 and A549/GR cells treated with FTH and GEF were detected by MTT method. The apoptotic rates and cell cycles of A549/GR cells treated with FTH and GEF were detected by Flow cytometry. The anti-tumor effects of flavonoids from FTH and GEF were assayed in A549/GR tumor-bearing mice. The expressions of proteins (PTEN, PI3K, p-PI3K, AKT, p-AKT) were detected by Western blot analysis. RESULTS: Compared with GEF group, FTH significantly enhanced the inhibition of GEF on the proliferation of A549/GR cells (P<0.05). Combination with FTH and GEF significantly increased the apoptosis of A549/GR cells which were arrested at the G0/G1 stage (P<0.05). The in vivo results showed that combination with FTH and GEF significantly inhibited the tumor growth of A549/GR in mice (P<0.05). Furthermore, this combination significantly downregulated the expressions of p-PI3K and p-AKT (P<0.05), but upregulated the expressions of PTEN (P<0.05). CONCLUSION: FTH increases the sensitivity to gefitinib by modulating PTEN/PI3K/AKT pathway in acquired GEF resistance of non-small cell lung cancer.
    Construction of mammary gland cell-specific SENP7 knockout mice by Cre-loxP system
    SUN Hong, HOU Jialin, CAI Jiaqin, ZHUANG Jie, WEI Xiaoxia
    2021, 26(4):  376-381.  doi:10.12092/j.issn.1009-2501.2021.04.003
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    AIM: To construct and identify the mammary gland cell-specific conditional knockout of SENP7 by the Cre-loxP system.  METHODS: The homozygous SENP7flox/flox mice were generated by crossing SENP7flox/+ mice. Genotypic identification was performed by PCR. SENP7flox/flox mice and MMTV-Cre mice had reproduced and genotyped respectively, then the two strains of mice were crossed. The MMTV-Cre×SENP7flox/flox mice were the required mouse model. Real-Time PCR, Western blot and HE staining were applied to identify the knockout effect of SENP7 and to observe the morphology of mammary gland tissue. RESULTS: PCR analysis selected MMTV-Cre×SENP7flox/flox mice. Compared to the MMTV-Cre×SENP7+/+ mice, expression levels of SENP7 mRNA and protein of mammary glands were significantly lower in MMTV-Cre×SENP7flox/flox mice, and the number of mammary glands was significantly reduced, suggesting the SENP7 knockout effect was obvious. CONCLUSION: The mammary cell-specific deletion of the SENP7 gene is successfully constructed by Cre-loxP system, which provides a novel target for studying the pathogenesis of breast tumors at animal level.
    Quantification of ambrisentan in human plasma by LC-MS/MS and its pharmacokinetic application
    MA Hong, LIU Jingyuan, JIN Hao, CHEN Yong, WANG Bo, LIU Wanhui, SI Duanyun, XIA Yuanyuan
    2021, 26(4):  382-388.  doi:10.12092/j.issn.1009-2501.2021.04.004
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    AIM: To establish an LC-MS/MS method to determine the concentration of ambrisentan in human plasma and apply it to the study of human pharmacokinetics.  METHODS: After extracting ambrisentan and internal standard from human plasma by liquid-liquid extraction, chromatographic separation was performed on a Waters Symmetry C18 column (4.6 mm×100 mm, 5 μm), organic phase: 40%methanol-60%acetonitrile, water phase: 5 mmol/L ammonium acetate-10% acetonitrile, flow rate: 0.5 mL/min, electrospray ionization source, multi-reaction monitoring, negative ion mode, monitoring ion pairs of ambrisentan and internal standard are m/z 377.1→301.2 and m/z 380.4→301.0, respectively. RESULTS: The linearity of ambrisentan was good in the concentration range of 2-2 000 ng/mL, the lower limit of quantification was 2 ng/mL, the intra-day precision was less than 2.72%, the inter-day precision was less than 8.98%, the matrix effect after normalization by internal standard was between 92.3% and 98.3%, and the extraction recoveries were between 74.6% and 80.5%. CONCLUSION: This method is sensitive, economical, and reliable. It is suitable for the determination of the concentration of ambrisentan in human plasma and meets the requirements of human pharmacokinetic studies.
    AHVAC-I reverses tumor growth of cancer-associated fibroblasats in gastric cancer
    JIANG Yuhua, ZHI Hui, LU Linming, TIAN Dahao, WANG Xiaoqing, GE Yu, XIE Shangfu, WANG Qi
    2021, 26(4):  389-394.  doi:10.12092/j.issn.1009-2501.2021.04.005
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    AIM: To explore whether Agkistrodon Halys venom antitumor component-I (AHVAC-I) affects the migration of gastric cancer cells by human primary gastric cancer-associated fibroblast (GCAFs).  METHODS: Tissue block culture and trypsin digestion were used to separate and culture human primary gastric cancer-associated fibroblasts (GCAFs);  the GCAFs-CMAHVAC-I  was collected after AHVAC-I treatment to culture the MKN28 cells. Migration was evaluated by wound-healing and Transwell assay. ELISA and RT-PCR were used to verify wether AHVAC-I can play a role in the production of CXCL12 from GCAFs.RESULTS: AHVAC-I can decrease the CXCL12 production from GCAFs (P<0.05). Cultured with GCAFs-CMAHVAC-I , the migration of MKN28 cells were significantly inhibited (P<0.05). CONCLUSION: AHVAC-I can inhibit the migration ability of gastric cancer cells MKN-28 by decreasing CXCL12 production from GCAFs, and is valuable for gastric cancer therapy.
    Two-stage estimation on adjustment for cross-over in oncology trials
    YU Quanji, NI Senmiao, YANG Min, ZHONG Zihang, ZHOU Jiawei, CAI Lixin, BAI Jianling, YU Hao
    2021, 26(4):  395-400.  doi:10.12092/j.issn.1009-2501.2021.04.006
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    AIM: To investigate the application of two-stage estimation (TSE) on adjustment for treatment switch in oncology trials.  METHODS: The theory and implementation of TSE method was described, and was applied to adjust the data from a two-arm randomized controlled trial of anti-tumor drugs. The changes of survival curves and hazard ratio of two groups after adjustment for cross-over were evaluated. In addition, the results of two-stage estimation and rank preserving structural failure time model (RPSFT) were compared. RESULTS: After adjustment for cross-over using TSE methods, the results showed that the median survival time of control group was shorter than the original one, and the hazard ratio was lower than the observed value. Moreover, TSE method showed similar results to rank preserving structural failure time model. CONCLUSION: The TSE method is relatively simple to use, reliable and has a good practice property in cross-over analysis of oncology trials. At the same time, it is necessary to pay attention to its application scopes. 
    OCTN2 gene polymorphisms affect the chemotherapeutic sensitivity of oxaliplatin in colorectal cancer
    LU Qiong, ZHU Haihong, QI Tingting, LI Guohua, TENG Xinqi, QU Qiang, QU Jian
    2021, 26(4):  401-407.  doi:10.12092/j.issn.1009-2501.2021.04.007
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    AIM: To explore the effect of OCTN2 gene polymorphism on the expression and function of OCTN2, as well as the sensitivity of SW480 cells to oxaliplatin.  METHODS: Four mutations of OCTN2 (F17L, E317K, S467C and P478L) transfected cell lines were constructed. Real-time RT-PCR and Western blot were used to detect the levels of OCTN2 mRNA and protein. The content of oxaliplatin was detected by HPLC. MTS assay was used to detect cell viability. RESULTS: The expression level of all mutant OCTN2 mRNA and protein was not significantly different from that of wild-type OCTN2. Oxaliplatin uptake experiments showed that there was no significant difference in Vmax and Km values between E317K and S467C cells (P>0.05), the Vmax of F17L decreased to 66.4% and Km value increased to 120.3%; the Vmax of P478L increased to 132.6%, and the value of Km decreased to 82.2%, and there were significant differences (P<0.05). The cell activity test showed that the IC50 value of all overexpressed OCTN2 cells decreased significantly. Compared with SW480-OCTN2 transfected cell lines, IC50 values of SW480 cells without transfection and F17L cell lines were up to 175% and 147%, while P478L cells decreased to 76.9%, which had significant differences (P<0.05). The IC50 value of E317K and S467C did not change significantly (P>0.05). CONCLUSION: The OCTN2 transporter gene F17L and P478L mutations can alter the uptake of oxaliplatin by OCTN2 transporter, thereby affecting the sensitivity of OCTN2-stably expression cell line to oxaliplatin.
    Bioequivalence of metformin hydrochloride sustained-release tablets in healthy subjects
    LI Xiaomin, JIN Hao, ZHOU Wenzhi, YANG Hanyue, ZOU Ting, GUO Jie, XU Pingsheng
    2021, 26(4):  408-413.  doi:10.12092/j.issn.1009-2501.2021.04.008
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    AIM: To study the bioequivalence of two metformin hydrochloride sustained-release tablets in Chinese healthy subjects.  METHODS: A randomized, open-label, two-period, crossover study design was adopted in the study. In fasting test 36 and in fed test 23 healthy subjects were given a single oral dose of metformin hydrochloride sustained-release tablet (0.5 g). The concentration of metformin in plasma was measured by HPLC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin 7.0 program, and statistical analysis were performed by using SAS9.4 statistics software. RESULTS: In the fasting test, the pharmacokinetic parameters of metformin of the test (T) and reference(R) preparation were as follow: Cmax were (700.6±191.1) and (694.5±169.2) ng/mL, AUC0-t were (4 858.7±1134.3) and (4 809.3±1 188.6) ng·h·mL-1, AUC0-∞ were (5 010.9±1 114.5) and (4 962.5±1 184.1) ng·h·mL-1. In the fed test, the pharmacokinetic parameters of T and R were as follow: Cmax were (738.4±121.9) and (738.0±128.7) ng/mL, AUC0-t were (7 558.3±1 271.8) and (7 761.5±1 486.0) ng·h·mL-1, AUC0-∞ were (7 713.7±1 275.5) and (7 924.3±1 506.30) ng·h·mL-1. In fasting condition, the 90% confidence interval (90%CI) of Cmax, AUC0-t and AUC0-∞ of metformin were 92.16%-111.56%, 93.36%-110.93% and 93.58%-110.39%. In fed condition, the 90%CI of Cmax, AUC0-t and AUC0-∞ of metformin were 96.74%-105.10%, 94.94%-101.71% and 95.00%-101.68%. All datas were in the area of 80.00%-125.00%. CONCLUSION: The two metformin hydrochloride sustained-release tablets were bioequivalent.
    Correlation between the expression of RON protein and CXC chemokine receptor 4 protein and abiraterone resistance in patients with castration-resistant prostate cancer
    WEI Songchang, YANG Hongqi, ZHANG Hongjuan, SHI Xiaoli, REN Kaiwen
    2021, 26(4):  414-422.  doi:10.12092/j.issn.1009-2501.2021.04.009
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    AIM: To study the correlation between the expression of recepteur d'origine nantais (RON) protein and CXC chemokine motif receptor 4 (CXCR4) protein and abiraterone resistance in patients with castration-resistant prostate cancer (CRPC). METHODS: From January 2017 to February 2020, 127 patients with CRPC who were treated with abiraterone in our hospital were selected. According to the status of drug resistance, they were divided into observation group (n=32, patients with abiraterone resistance) and control group (n=95, patients in remission). Immunohistochemistry and Western blot analysis were used to compare the expression of RON and CXCR4 protein between the two groups. Logistic regression analysis was used to conduct single-factor and multi-factor analysis of RON, CXCR4 protein and drug resistance, and receiver operating characteristic curve (ROC) and area under ROC (AUC) were used to analyze the value of RON and CXCR4 protein in predicting drug resistance. In addition, RON and CXCR4 inhibitors were added to abiraterone-resistant cell lines. The effects of the two on the apoptosis indicators of abiraterone resistance [caspase-3, caspase-9, apoptosis rate] were observed. RESULTS: Immunohistochemistry showed that the positive expression rate of RON in the observation group (71.88%, 23/32) was higher than that of the control group (27.37%, 26/95). The positive expression rate of CXCR4 in the observation group (65.63%, 21/32) was higher than that of the control group (12.63%, 12/95). Western blot detection showed that the RON and CXCR4 proteins in the observation group were higher than those in the control group (P<0.05). RON and CXCR4 protein were positively correlated with drug resistance (P<0.05). After adding RON and CXCR4 inhibitors, the expression of RON and CXCR4 was successfully inhibited, and the rates of caspase-3, caspase-9 and cell apoptosis were higher than those of abiraterone-resistant cell lines (P<0.05). The cell migration and invasion detected by Transwell experiment showed that inhibiting the expression of RON and CXCR4, the number of cell migration and invasion cells were significantly reduced (P<0.05). The AUC of RON protein predicting abiraterone resistance was 0.789, the cut-off value was>4.11, the sensitivity was 84.37%, and the specificity was 61.05% (P<0.05). The AUC of abiraterone resistance predicted by CXCR4 protein was 0.825, the cutoff value was>3.42, the sensitivity was 75.00%, and the specificity was 80.00% (P<0.05). The AUC of RON+CXCR4 protein predicting abiraterone resistance was 0.884 (95%CI: 0.815-0.934), the sensitivity was 87.50%, and the specificity was 83.16% (P<0.05). CONCLUSION: The expression of RON and CXCR4 protein in CRPC patients increases significantly, which is closely related to the resistance of Abiraterone in patients and is expected to become a marker for predicting drug resistance. Inhibiting the expression of RON and CXCR4 proteins can promote the apoptosis of CRPC abiraterone resistant cells.
    Advances in risk assessment systems from non-clinical to clinical arrhythmia stages
    XU Runze, HAN Jingjing, LI Wenqian, YANG Jin
    2021, 26(4):  423-433.  doi:10.12092/j.issn.1009-2501.2021.04.010
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    The withdrawal of drugs from the market due to serious adverse reactions arising from the risk of cardiac arrhythmia has been a major concern for regulatory authorities in recent years. In 2005, the International Council for the Harmonisation of Registration of Medicinal Products for Human Use (ICH) issued preclinical S7B and clinical E14 guidelines for the evaluation of arrhythmia risk. The former includes in vitro hERG experiments and in vivo animal-based QT studies, while the latter is the TQT study (thorough QT study, TQT study). The high cost and conservative results of TQT studies have led to the introduction of new alternative methods, and the E14 guidelines were revised in 2015 and introduced concentration-QT analysis (C-QTc), based on the PK/PD (pharmacokinetics/pharmacodynamics) concept, by making full use of high-quality double-negative data from the non-clinical phase (double-negative, low risk of hERG tests at high clinical exposure, and low risk of QTc prolongation in vivo QTc study) makes it possible to substitute TQT studies based on specific situations. This article reviews the history of the development of E14 and its latest developments, analyses the specific situations in which C-QT can replace TQT studies through case studies, introduces the preclinical-clinical arrhythmia risk stage assessment system and compares the drug assessment process and decision making under different versions of E14 guidelines, with a view to providing a reference for the arrhythmia risk assessment system in China.
    Erythropoietin's biological function and source
    YANG Huan, SHI Yuhong, RAN Haifeng, CHEN Yijin, XU Xiaoyu
    2021, 26(4):  434-443.  doi:10.12092/j.issn.1009-2501.2021.04.011
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    Erythropoietin is an endogenous 34 000 glycoprotein hormone composed of 165 amino acids. EPO is mainly derived from the liver of the fetus and synthesized in the kidney after birth, but is secreted by the liver, kidney, brain, reproductive system, bone marrow macrophage and mammary gland. The production of EPO is regulated by hypoxia-inducible factors. EPO can significantly stimulate the proliferation and survival of red blood cells and promote hematopoiesis; it has been used clinically to treat chronic renal anemia, anemia caused by bone marrow tumors and myelodysplasia. EPO has a wide range of physiological functions and it is found in all systems of animal life. Apart from promoting hematopoiesis, EPO also promotes angiogenesis, and shows brain protection, kidney protection, heart protection, regulation of metabolism, regulation of inhalation, protection of the digestive system and reproductive system. Animals without EPO can hardly survive. It illustrates that EPO plays an important role in life.
    Research progress of melatonin on pulmonary hypertension
    WANG Rui, PAN Jinjin, LI Hua, YUAN Yuhui
    2021, 26(4):  444-448.  doi:10.12092/j.issn.1009-2501.2021.04.012
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    Pulmonary hypertension is a severe disease with a wide spectrum of underlying etiologies, which was characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, and eventually leads to right heart dysfunction and even death with a high mortality rate. Melatonin, as a neuroendocrine hormone, is produced primarily by the pineal gland. Melatonin, a pleotropic molecule, plays a key role in the pathophysiology of various cardiovascular diseases.The effects of melatonin which can attenuate pulmonary vascular remodeling and pulmonary artery pressure have been widely concerned by researchers in recent years. This review summarized the progress of melatonin on pulmonary hypertension.
    New perspectives on the principle of intention to treat in clinical trials#br#
    HUANG Lihong, WANG Ling, YAN Fangrong, WEI Zhaohui, ZHAO Yang, XIA Jielai, CHEN Feng
    2021, 26(4):  449-453.  doi:10.12092/j.issn.1009-2501.2021.04.013
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    The intention to treat (ITT) principle is widely applied in the randomized controlled trials (RCTs), which is based on the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. With the development and progress of clinical trials, ITT principle needs to be reinterpreted. In the standard definition of ITT principle, the intentional grouping of subjects does not specifically refer to randomization, but rather to planned treatment regimen. In non-randomized clinical trials, that subjects agree to be included in a certain treatment regimen is also a type of intention. ITT principles can be applied to evaluate the effectiveness of treatment regimens under patient/doctor determined intentionality in single-arm clinical trials and non-randomized RWS (real world study, RWS). In the practical application, the grouping strategy based on ITT principle should be considered comprehensively according to the research purpose.
    Research progress in clinical trials of targeted drugs for gastric cancer
    Pazilaiti YASEN, YUAN Hao, LU Hong, ZHENG Ya, WANG Yuping, ZHOU Yongning
    2021, 26(4):  454-461.  doi:10.12092/j.issn.1009-2501.2021.04.014
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    In the past several years, chemotherapy, as the best treatment option for advanced gastric cancer, however, was associated with adverse events and high resistance rates. Recently, molecular targeted drugs have gradually come into notice of clinical researchers due to the advantages of selectively killing tumor cells and less adverse events. Many clinical trials have confirmed targeted drugs targeting receptor tyrosine kinases combined with chemotherapy drugs could provide more survival benefits and might be effective for the treatment of gastric cancer. This article aims to demonstrate the progress in clinical trials of targeted therapeutic drugs for gastric cancer.
    Research progress on extraction methods and pharmacological activities of polysaccharide from traditional Chinese herb compound
    JING Yongshuai, ZHANG Yuwei, WU Lanfang, ZHANG Ruijuan, MA Yunfeng, ZHANG Danshen
    2021, 26(4):  462-468.  doi:10.12092/j.issn.1009-2501.2021.04.015
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    Traditional Chinese herb compound is a prescription formulated according to the theory of Chinese medicine, and it is a commonly used method of Chinese medicine. As one of the main active ingredients, the extraction methods of polysaccharides from traditional Chinese herb compound include solvent extraction, ultrasonic assisted extraction, microwave assisted extraction and microbial fermentation extraction. The traditional Chinese herb compound polysaccharide has antitumor, immunoregulatory, intestinal mucosa repair, hypoglycemic, antiviral, antioxidant and other pharmacological activities. In this paper, the extraction methods of polysaccharides from traditional Chinese herb compound and its pharmacological activities were summarized, so as to provide scientific evidence for a better development and utilization of traditional Chinese herb compound polysaccharide. 
    Research progress of transient receptor potential ion channels and psoriasis
    ZHANG Xiaoli, LIU Yi
    2021, 26(4):  469-473.  doi:10.12092/j.issn.1009-2501.2021.04.016
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    The occurrence of psoriasis mainly involves abnormal cellular immune system and the abnormal proliferation and differentiation of keratinocytes. Recent studies have found that transient receptor potential (TRP) ion channels are related to the etiology of psoriasis and play an important role in the pathophysiological process of psoriasis. Using inhibitors or activators of partial TRP channels can improve or alleviate the symptoms of psoriasis, suggesting that partial TRP channels may be new targets for psoriasis treatment. This article mainly reviews the relationship between TRP channels and etiology of psoriasis, and the research advancement of TRP channels as treatment targets for psoriasis.
    Clinical research progress of afatinib therapy for lung cancer
    HUANG Yiting, SHEN Aizong
    2021, 26(4):  474-480.  doi:10.12092/j.issn.1009-2501.2021.04.017
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    Afatinib, a second-generation oral tyrosine kinase inhibitor (TKI), is suitable for first-line treatment of advanced non-small-cell lung cancer (NSCLC) and second-line treatment of squamous NSCLC. At present, a large number of strong clinical research data has confirmed the efficacy and safety of afatinib. Therefore, this article reviews the mechanism of action, pharmacokinetic clinical efficacy, combination of drugs, adverse reactions and dose adjustment of afatinib in order to provide ideas for individual rational drug use guidance.