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临床药理研究所


学术研究

在科学研究方面,主要研究方向为临床药理研究、新药开发研究等。

在临床药理研究方面,主要进行药物代谢与药物动力学、CYP2E1与肿瘤等炎症相关疾病研究等,目的是为临床个体化用药、以及肿瘤等炎症相关疾病防治提供依据。在药物代谢与药物动力学研究方面,创建了国内领先、国际先进的肝脏CYP450药物代谢的体外研究技术平台,对CYP450的生理和病理进行了系统研究,证明CYP450基因多态性以及酶含量对药物代谢影响的有限性,为指导临床个体化用药奠定了基础;证明肝癌患者肝CYP450各亚型代谢活性改变不一,有的降低,有的不变,有的增高;发现CYP2E1为炎症反应中的新靶点,证明其与肿瘤等炎症相关性疾病的发生发展有关,并研发了CYP2E1特异性抑制剂。

上述研究得到了重大新药创制国家科技重大专项和6项国家自然科学基金项目的资助,所创制的国家1.1类抗脑缺血新药正在进行临床研究,相关研究成果被编入人民卫生出版社出版的研究生教材《高级药理学》中。

在新药研发方面,在重大新药创制国家科技重大专项支持下,完成了抗脑缺血新药布罗佐喷钠的临床前研究,并获得了国家食品药品监督管理总局的新药临床研究批件,现正在进行临床研究,有望开发成为具有我国自主知识产权的国家一类新药;另外,新近发现CYP2E1是炎症反应中的新靶点,CYP2E1为肿瘤等炎症相关疾病发生发展的新机制,CYP2E1抑制剂在炎症相关疾病的防治方面展现出较好的开发应用前景。

上述研究多为跨学科研究,与国内外开展了广泛合作研究,如澳大利亚悉尼大学、蛋白质组学国家重点实验室、国家人类基因组南方研究中心等。

近年来,主持完成了重大新药创制国家科技重大专项、国家自然科学基金等多项国家级和省部级科研项目,发表了200余篇研究论文,主持获得了河南省科技进步二等奖3项等。由于成绩突出,研究团队被评为河南省科技创新团队和郑州大学协同创新中心。

1:近5年主持的10项代表性科研项目

1. 乔海灵,等. 新型抗脑缺血药物6--3-正丁基-13H-异苯并呋喃酮的研发(2012ZX09103-101-011),国家十二五计划重大新药创制科技重大专项,143.97万,2012.01-2015.12

2. 乔海灵,等. 基于肝癌患者CYP2E1活性增高研究CYP2E1特异性抑制剂(81872931),国家自然科学基金,57万元, 2019.01-2022.12

3. 乔海灵,等. 基于肝癌病人CYP2E1活性增高研究亚硝胺类致肝癌作用(81673507),国家自然科学基金,65万元, 2017.01-2020.12

4. 乔海灵,等. 人肝微粒体CYP代谢药物个体差异技术平台的建立及关键技术研究,(81473279),国家自然科学基金,70万元, 2015.01-2018.12

5. 郜娜,等. 乙醇脱氢酶I诱导肝星状细胞活化和PAI-1表达从而促进肝纤维化(U1804169),国家自然科学基金,49万元, 2019.01-2021.12

6. 温强,等. FoxO3aPC9细胞中对吉非替尼耐药性的调控机制(U1304815),国家自然科学基金地区联合项目,30万,2014.01-2016.12

7. 乔海灵,等. 以人CYP2D6CYP3A4多态性酶关键氨基酸为靶点研究黄芩苷的特异性酶抑作用(134200510019),河南省科技创新杰出人才项目,50万,2013.01-2015.12

8. 乔海灵,等. 新药药理研究与评价(131PCXTD604),郑州市科技创新团队,郑州市科学技术局,80万元,2013.1-2015.12

9. 乔海灵,等.肝脏药物代谢与个体化医学。郑州大学协同创新中心,200万元,2015.01-2018.12

10. 郭玉忠,等. 唐草片对伊立替康毒性的保护作用。横向课题,11.5万元,2015.01-2017.12

2:近5年来发表的20篇代表性论文(郑州大学临床药理研究所均为第一作者和通讯作者单位)

1. Fang Yan, Wang Tong, Guo Yuan-Yuan, Zhang Hai-Feng, Wen Qiang, Xing Yu-Rong*, Gao Na*, Qiao Hai-Ling*. From Genotype to Phenotype: Content and Activities of Cytochromes P450 2A6 in Human Liver In Vitro and Predicted In Vivo. J Pharmacol Exp Ther 2020, 372:320-330 JCR一区)

2. Guo Yuan-Yuan, Xu Chen, Fang Yan, Wang Cai-E, Gao Na, Wen Qiang, Qiao Hai-Ling*. High CYP2E1 activity aggravates hepatofibrosis by limiting macrophage polarization towards the M2 phenotype. Mol Carcinog 2019; 58(8):1481-1491 (中科院二区)

3. Wen Qiang, Jiao Xin-Wei, Kuang Fei, Hou Bei-Bei, Zhu Ya-Jing, Guo Wen-Yu, Sun Guang-Xin, Ba Yu-Feng, Yu Dan-Dan, Wang David, Zhang Fa-Ya, Qiao Hui- Chao, Wang Shuo-Lin, Tang Shu*, Qiao Hai-Ling*. FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signaling. EBioMedicine 2019, 40:198-209 JCR一区)

4. Xiao Kang, Gao Jie, Weng Shi-Jia, Fang Yan, Gao Na, Wen Qiang, Jin Han, Qiao Hai-Ling*. CYP3A4/5 activity probed with testosterone and midazolam: Correlation between two substrates at the microsomal and enzyme levels. Mol Pharm 2019, 16(1): 382-392 JCR一区)

5. Fang Yan, Gao Jie, Wang Tong, Tian Xin, Gao Na, Zhou Jun, Zhang Hai-Feng, Wen Qiang, Jin Han, Xing Yu-Rong*, Qiao Hai-Ling*. Intraindividual Variation and Correlation of Cytochrome P450 Activities in Human Liver Microsomes. Mol Pharm 2018, 15(11):5312-5318 JCR一区)

6. Gao Na, Li Jing, Li Ming-Rui, Qi Bing, Wang Zhao, Wang Gao-Ju, Gao Jie, Qiao Hai-Ling*. Higher Activity of Alcohol Dehydrogenase Is Correlated with Hepatic Fibrogenesis. J Pharmacol Exp Ther 2018,367(3):473-482 JCR一区)

7. Gao Jie, Wang Zhao, Wang Gaojv, Gao Na, Li Jing, Zhang Yun Fei, Zhou Jun, Zhang HongXin, Wen Qiang, Jin Han, Qiao HaiLing*. From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor. Mol Carcinog 2018, 57(10):1371-1382 (中科院二区)

8. Xu Chen, Gao Jie, Zhang Hai-Feng, Gao Na, Guo Yuan-yuan, Fang Yan, Wen Qiang, Qiao Hai-Ling*. Content and Activities of UGT2B7 in Human Liver In Vitro and Predicted In Vivo: A Bottom-Up Approach. Drug Metab Dispos 2018, 46 (9):1351-1359 JCR一区)

9. Gao Jie, Wang Zhao, Wang Gao-Ju, Zhang Hong-Xin, Gao Na, Wang Jie, Wang Cai-E, Chang Zhao, Fang Yan, Zhang Yun-Fei, Zhou Jun, Jin HanQiao Hai-Ling*. Higher CYP2E1 activity correlates with hepatocarcinogenesis induced by diethylnitrosamine. J Pharmacol Exp Ther 2018, 365(2):398-407 JCR一区)

10. Gao Jie, Wang Jie, Gao Na, Tian Xin, Zhou Jun, Fang Yan, Zhang Hai-Feng,Wen Qiang, Jia Lin-Jing, Zou Dan, Qiao Hai-Ling*. Prediction of cytochrome P450-mediated drug clearance in humans based on the measured activities of selected CYPs. Biosci Rep. 2017;37(6)piiBSR20171161

11. Gao Yuan, Li Miao, Wang Yan, Li Zhenqi, Fan Chenyu, Wang Zheng, Cao Xinyu, Chang Junbiao*, Qiao Hailing*. Protective Effects of Sodium (±)-5-Bromo-2-(α-Hydroxypentyl) Benzoate in a Rodent Model of Global Cerebral Ischemia. Front Pharmacol 2017;8:691 JCR一区)

12. Gao Yuan, Wang Yan, Li Miao, Liu Yali, Chang Junbiao*, Qiao Hailing*. Preventive and therapeutic effect of brozopine on stroke in Dahl Salt-sensitive hypertensive rats. Brain Res 2017, 1672:137-147JCR一区)

13. Gao Jie, Tian Xin, Zhou Jun, Cui Ming-Zhu, Zhang Hai-Feng, Gao Na, Wen Qiang, Qiao Hai-Ling*. From genotype to phenotype: cytochrome P450 2D6-mediated drug clearance in humans. Mol Pharm 2017, 14(3):649-657 IF 4.556 JCR一区)

14. Tian Xin, Li Hong-Meng, Wei Jing-Yao, Liu Bing-Jie, Zhang Yu-Hai, Wang Gao-Ju, Chang Jun-Biao, Qiao Hai-Ling*. Preclinical pharmacokinetics, tissue distribution, and plasma protein binding of sodium (±)-5-bromo-2-(α-hydroxypentyl) benzoate (BZP), an innovative potent anti-ischemic stroke agent. Front Pharmacol 2016, 7:255 JCR一区)

15. Gao Na, Tian Xin, Fang Yan, Zhou Jun, Zhang Haifeng, Wen Qiang, Jia Linjing, Gao Jie, Sun Bao, Wei Jingyao, Zhang Yunfei, Cui Mingzhu, Qiao Hailing*. Gene polymorphisms and contents of cytochrome P450s have only limited effects on metabolic activities in human liver microsomes. Eur J Pharm Sci 2016, 92:86–97 JCR一区)

16. Zhang Hai-Feng, Li Zhi-Hui, Liu Jia-Yu, Liu Ting-Ting, Wang Ping, Fang Yan, Zhou Jun, Cui Ming-Zhu, Gao Na, Tian Xin, Gao Jie, Wen Qiang, Jia Lin-Jing, Qiao Hai-Ling*. Correlation of Cytochrome P450 Oxidoreductase Expression with the Expression of 10 Isoforms of Cytochrome P450 in Human Liver. Drug Metab Dispos 2016, 44(8):1193-200 IF 4.242 JCR一区)

17. Zhang Hai-Feng, Wang Huan-Huan, Gao Na, Wei Jun-Ying, Tian Xin, Zhao Yan, Fang Yan, Zhou Jun, Wen Qiang, Gao Jie, Zhang Yang-Jun, Qian Xiao-Hong, Qiao Hai-Ling *. Physiological content and intrinsic activities of 10 cytochrome P450 isoforms in human normal liver microsomes. J Pharmacol Exp Ther 2016, 358(1):83–93 IF 3.867 JCR一区)

18. Zhou JunWen QiangLi SaifeiZhang YunfeiGao NaTian XinFang YanGao JieCui MingzhuHe XiaopeiJia LingjingJin HanQiao Hailing*. Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma. Oncotarget 20167(31): 50612-50622 IF 5.168 JCR一区)

19. Tian Xin, Liu Bing-Jie, Zhang Yuhai, Li Hong-Meng, Wei Jing-Yao, Wang Gao-Ju, Chang Jun-Biao, Qiao Hai-Ling*. LC-MS/MS Analysis and Pharmacokinetics of Sodium ±)-5-Bromo-2-(α-hydroxypentyl) Benzoate (BZP), an Innovative Potent Anti-Ischemic Stroke Agent in Rats. Molecules 2016, 21(4), 501-12

20. Zhang Hai-Feng, Gao Na, Tian Xin, Fang Yan, Zhou Jun, Wen Qiang, Xu Bin-Bin, Qi Bing, Gao Jie, Li Hong-Meng, Jia Lin-Jing, Qiao Hai-Ling*. Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo. Sci Rep 2015; 5:17671 IF 5.228 JCR一区)

 

3 5部代表性著作

1. 乔海灵,主编,临床药理学(第2版)(全国高等医药院校十三五规划教材),高等教育出版社,书号:ISBN 978-7-04-047856-3 2017.7

2. 乔海灵,编委,药理学(第四版)(十二五普通高等教育本科国家级规划教材),科学出版社,书号:ISBN 978-7-03-047155-0, 2016.06

3. 乔海灵,编委,药理学(第四版)学习指导(十二五普通高等教育本科国家级规划教材),科学出版社,书号:ISBN 978-7-03-047998-3,2016.06

4. 乔海灵,编委. 药理学(第3版)(十二五普通高等教育本科国家级规划教材,全国高等学校医学规划教材),高等教育出版社,书号:ISBN 978-7-04-047167-0,2018.1

5. 乔海灵,编委,药理学(第9版)(国家卫生健康委员会十三五规划教材),人民卫生出版社,书号:ISBN 978-7-117-26604-82018

4 3项代表性成果

1. 乔海灵,郜娜,田鑫,郭玉忠,贾琳静,杨静,高孟哲,王勇,邹丹. 劳拉西泮等13种新药的血药浓度分析及在国人体内的药动学研究,河南省科技进步二等奖(证书号:2011-J-164-R01/09)2012.01

2. 乔海灵,田鑫,郜娜,贾琳静,郭玉忠,胡玉荣,杨静,宋建伟,李瑜,杜玉明,杨再刚,彭涛,李华. 质子泵抑制剂在CYP2C19不同基因型国人体内的药代动力学。 河南省科技进步二等奖(证书号:2008-J-159-R01/10),2008.11

3. 乔海灵,主编. 临床药理学(第2版)(全国高等医药院校十三五规划教材),高等教育出版社,书号:ISBN 978-7-04-047856-3 2017.7出版,获2019年郑州大学优秀教材特等奖