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

Table of Content

    Volume 26 Issue 9
    26 September 2021
    Tangshen formula improves cholesterol uptake and efflux of macrophages induced by high lipid via activating PGC-1α/LXR/ABCA1 pathway
    XU Ke, GAO Junwei, LIU Peng, SHEN Zhengri, JIA Hui, WU Chenguang, TIAN Feng, WANG Lifan, LI Ping
    2021, 26(9):  978-985.  doi:10.12092/j.issn.1009-2501.2021.09.002
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    AIM: To observe the effects of Tangshen formula (TSF) treatment on lipid efflux and uptake in sodium palmitate (PA) induced RAW264.7 macrophages.  METHODS: After 200 μmol/L PA induced RAW264.7 macrophages, TSF and PGC-1α-siRNA were given to intervene respectively. The lipid content in the cells was detected by ELISA kit; intracellular lipid droplet deposition was detected by BODIPY 493/503 and Filipin staining. Western blot and Real-time PCR were used to detect the expression of PGC-1α, LXR, ABCA1 and CD36. RESULTS:  TSF diminished the levels of TC, TG and intracellular lipid droplet deposition in PA-induced RAW264.7 macrophages. Western blot and Real-time PCR analysis showed that TSF could up-regulate the expression of PGC-1α, LXR, ABCA1 and down-regulate the expression of CD36. Furthermore, silencing PCG-1α by SiRNA significantly suppressed the effects of upregulating the expression of PGC-1α, LXR and ABCA1, and downregulating the CD36 expression with TSF treatment. CONCLUSION: TSF may extenuate intracellular lipid droplet deposition in macrophages by upregulating cholesterol efflux through activating the PGC-1α/LXR/ABCA1 pathway and inhibiting lipid uptake through down-regulateing the expression of CD36.
    Chronopharmacokinetics research of helicid and its metabolites
    JIA Yuanwei, SHEN Jie, CHU Jiru, ZHANG Cuifeng, XIE Haitang, YANG Bin, LI Xianghong, ZHENG Dandan, ZHAO Jinghui
    2021, 26(9):  986-994.  doi:10.12092/j.issn.1009-2501.2021.09.003
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    AIM: To study chronopharmacokinetics of helicid and its metabolites. METHODS: An HPLC-MS method for simultaneous determination of helicid and its three phase I metabolites were established and validated. At 8∶00, 14∶00 and 0∶00, the rats were given helicid 50 mg/kg by gavage, respectively. Blood samples were collected from ophthalmic venous plexus. Then plasma concentration was measured. Pharmacokinetic behaviors of the original drug and its metabolites after administration at different time points were calculated and compared. RESULTS: This established HPLC-MS/MS method was successfully applied to simultaneous determination of helicid and its three metabolites in rat plasma after intragastric administration. Using AUC(0-t) as evaluation index of degree of absorption, the original drug, oxidation product, and reduction product in the 8∶00 administration group were all >0∶00 administration group and >14∶00 administration group; at the same time point compared with the metabolites, 8∶00 administration group, 14∶00 administration group, and 0∶00 administration group were: original drug>reduced metabolite>oxidized metabolite. Cmax original drug 0∶00 administration group>8∶00 administration group>14∶00 administration group, reduction and oxidation metabolites were 8∶00 administration group>14∶00 administration group>0∶00 administration group. Tmax original drug and reduced metabolite 8∶00 administration group>14∶00 administration group>0∶00 administration group, oxidation metabolite 8∶00 administration group>0∶00 administration group>14∶00 administration group. Clearance characterized by CLz/F, the original drug, reduction metabolite and oxidation metabolite were all 14∶00 administration group>0∶00 administration group>8∶00 administration group. CONCLUSION: The three specific time points selected in this study, absorption and metabolism process of helicid and its metabolites showed great differences. The absorption degree of administration at 8∶00 was greater than the other two time points (P<0.01), and the elimination of the original drug and metabolites from the body at 14∶00 was much faster than that at other time points (P<0.01).
    Effects of different doses of dexamethasone on angiotensin II, its receptors and NO levels in septic kidney injury rats
    ZHAN Zhuqin, BAI Haitao
    2021, 26(9):  995-1004.  doi:10.12092/j.issn.1009-2501.2021.09.004
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    AIM: To investigate the changes of angiotensin II, its receptors and nitric oxide (NO) expression in rats with acute kidney injury (AKI) induced by endotoxin (LPS) and to assess the efficacy of different doses of dexamethasone (DXM).  METHODS: Wistar rats were randomly divided into five groups as follows: control group (NC), LPS group, and DXM treatment groups of different doses of DXM (0.5, 1.0 and 5.0 mg/kg). The AKI group was injected with LPS through the lateral tail vein, and the intervention group was given different doses of DXM after LPS injection. Tissue samples were collected at 2, 6, 12 and 24 h after treatment. Serum creatinine and urea nitrogen levels were determined by automatic biochemical analyzer. H&E staining was used to observe renal histopathology. Serum TNF-α and MIP-1α levels were determined by ELISA. The expression of the angiotensin receptor 1 (AT1R) and angiotensin receptor 2 (AT2R) proteins were detected by Western blot and immunohistochemistry. Nitrate reductase was used to detect NO changes in the serum and renal tissues. RESULTS: The serum levels of serum TNF-α, MIP-1α, creatinine, and urea nitrogen were significantly increased in the LPS group compared with the control group (P<0.05). A similar trend was also observed in the levels of plasma and renal tissue AngII, renal tissue AT2R, serum and renal tissue NO (P<0.05). The expression of AT1R in renal tissue was significantly decreased in the LPS group compared with the control group (P<0.05). Pathological analysis showed that glomerular neutrophil infiltration and renal tubular epithelial cells swelling, vacuolar degeneration and necrosis in the LPS group. Prolongation LPS treatment resulted in more significant kidney damage. The serum levels of TNF-α, MIP-1α, creatinine, and urea nitrogen were significantly decreased in the DXM group compared with the LPS group (P<0.05). A similar trend was also observed in the levels of plasma and renal tissue AngII, renal tissue AT2R, serum and renal tissue NO in the DXM group (P<0.05). The expression of AT1R in renal tissue was significantly increased (P<0.05) in the DXM group compared with the LPS group, indicating the alleviation of kidney injury. Amongst these biomarkers, the levels of serum TNF-α, MIP-1α, plasma AngII showed the most significant decrease in the high dose DMX group (P<0.05). The levels of serum creatinine, urea nitrogen, kidney NO showed more significant decreases in the low and medium dose DMX groups (P<0.05). The levels of kidney AngII to dose and AT1R showed the most significant decrease in medium and high dose DXM groups (P<0.05). The levels of kidney AT2R and serum NO were not significantly different between the DXM treatment groups.  CONCLUSION: LPS can induce AKI in rats that can be mitigated by DXM. The mechanism of DXM in protection against AKI may be related to the down-regulation of inflammatory factors such as AngII, AT2R, and NO, and the up-regulation of AT1R expression. Different doses of dexamethasone have different intervention effects for different effector molecules.
    Atractyloside targets the area of action of oncoprotein BORIS to inhibit cancer cell proliferation
    LIU Chen, FANG Mengdie, XU Hao, LI Chao, REN Juan, ZUO Bowen, ZHANG Yanmei
    2021, 26(9):  1005-1013.  doi:10.12092/j.issn.1009-2501.2021.09.005
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    AIM: To analyze the binding area of atractyloside targeting oncoprotein BORIS to inhibit cancer cell proliferation.  METHODS: DNAMAN comparison sequences were used to find the conserved regions of BORIS. Conservative regions were elected and the structure were predicted using SWISS-MODEL. ChemBio3D Ultra was used for minimum structure quantification, and Autodocking for molecular docking. The BORIS of the corresponding segment were overexpressed for verification. RESULTS: BORIS-N end had relatively conserved regions and high-level structures in the biological evolution process. The N-terminal of human-derived BORIS was the main action area we speculated, especially the 70th to 97th amino acids, and the site that binded preferentially to atractyloside after molecular docking was the 96th position (Glutamine), and this area would inhibit cell proliferation. CONCLUSION: BORIS-N terminal and atractyloside have an action area, and this segment has an important effect on cell proliferation, which is of great significance for the future screening of targeted drugs.
    Establishment of population pharmacokinetics model of vancomycin in patients with Neutropenia
    LIN Liangmo, FU Xiangjun, ZHONG Lili, WANG Hefang, WU Qiongshi, XIAO Jian
    2021, 26(9):  1014-1022.  doi:10.12092/j.issn.1009-2501.2021.09.006
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    AIM: To establish a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases who developed neutropenia.  METHODS: Patients from department of hematology with neutropenia in our hospital were taken into oue study.The patients (n=77) were performed trough and peak serum concentration of vancomycin, and their clinical data and medication information were collected. The Nonlinear mixed effect modeling approach (NONMEM) was used to establish the PPK model of those patients and model assessment and validation was carried out. Goodneess of fit plots and visual predictive check plus Bootstrap approach were used to assess validate our model. RESULTS: The model was a two compartment model, the final formulas were: clearance rate CL=6.84×(BW/70)0.75×(CLCR/116)0.895 ×exp(η1), distribution volume of central ventricle V1=20.5×(BW/70)×exp(η2), transport rate Q=15.2×(BW/70)0.75×exp(η3), distribution volume of peripheral ventricle V2=50×(BW/70)×exp(η4), (BW was body weight, CLCR was creatinine clearance rate). Additionally 15 patients with neutropenia were included to conduct external validation, and it showed good stability and accuracy. CONCLUSION: The establishment of PPK model of vancomycin in patients with hematologic diseases who developed neutropenia is helpful to realize the individualized application of vancomycin in this population.
    Construction of informatization system of drug clinical trials ethical review based on cloud architecture
    SHE Zhihua, CHEN Zhou, LIANG Songyue
    2021, 26(9):  1023-1030.  doi:10.12092/j.issn.1009-2501.2021.09.007
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    AIM: To improve the quality, efficiency, standardization and prospective management of ethical review of drug clinical trials in our hospital through the information system construction of ethical review of drug clinical trials.  METHODS: The entire information system was designed based on the cloud architecture, enabling all ethics review applicants and ethics committees to use the same system for online registration and online business, which provided an information solution for the business model of regional ethics committees and multi-center ethics mutual recognition. RESULTS: Through the construction of ethical review platform of cloud architecture, the paperless and electronic management of ethical data have been realized, and online meeting review, tracking review and remote video conference have been realized on mobile and computer terminals. CONCLUSION: The information construction of ethical review system improves the efficiency and management level of ethical review in drug clinical trials.
    Application of medical failure mode and effect analysis in blood sample management in phase I clinical trials#br#
    SONG Yan, GAO Linyan, ZHANG Yanping, LI Xiang, ZHANG Lan
    2021, 26(9):  1031-1036.  doi:10.12092/j.issn.1009-2501.2021.09.008
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    AIM: To explore the application effect of medical failure mode and effect analysis in the blood sample management of phase I clinical trials, and to provide a basis for improving the quality of blood sample management.  METHODS: Convenient sampling was used to draw blood samples from healthy subjects in phase I clinical trials as the research objects. According to whether the medical failure mode and effect analysis method was implemented, they were divided into 3 080 control groups and 3 064 observation groups. The unqualified rate of blood samples, the number of unqualified items, the satisfaction of subjects and the passing rate of the researcher's examination between the two groups were compared. RESULTS: The unqualified rate of blood samples in the control group was 1.95%, and the unqualified rate of blood samples in the observation group was 0.59%. The difference between the two groups was statistically significant (P<0.05).  The number of unqualified items in the blood samples of the observation group was lower than that of the control group, and the difference between the two groups was statistically significant (P<0.05). The satisfaction of subjects in the observation group and the passing rate of the investigator were higher than those in the control group, and the difference between the two groups was statistically significant (P<0.05). CONCLUSION: The implementation of medical failure mode and effect analysis not only provides qualified biological samples for the detection and analysis of drug concentration in clinical trials, but also enhances the standardization and specialization of researchers, and contributes to the improvement of the overall quality of clinical trials.
    Multiple imputation of missing data in clinical longitudinal studies and its sensitivity analyses
    JIAO Zhigang, FAN Ru, XU Biyun, CHEN Sizhen, ZANG Yiteng, WANG shiyuan, CHEN Bingwei
    2021, 26(9):  1037-1041.  doi:10.12092/j.issn.1009-2501.2021.09.009
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    AIM: To guide the multiple imputation of missing data in clinical longitudinal studies and its sensitivity analyses, and highlight the importance of sensitivity analyses by taking the clinical trial of Qizhitongluo Capsule in treating ischemic stroke as an example.  METHODS: To implement PROC MI process in SAS to perform multiple imputation and its sensitivity analysis. RESULTS: In the example, after multiple imputation, improvements in lower limb motor scores of the Qizhitongluo group were greater than those of the placebo group (all P<0.01), and the results of two sensitivity analyses under "missing not at random" were consistent with those under "missing at random".CONCLUSION: Multiple imputations combined with sensitivity analyses can ensure a robust result. It is recommended that clinical researchers perform sensitivity analyses after filling missing data.
    Application of nalbuphine in ultrasound-guided transvaginal oocyte retrieval and its effect on embryo quality and pregnancy outcome
    LIU Xin, LENG Yufang, ZHANG Xuehong, ZHANG Lili, ZHANG Mengjie, QU Shanshan, XIE Jianqin, WANG Yiqing
    2021, 26(9):  1042-1047.  doi:10.12092/j.issn.1009-2501.2021.09.010
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    AIM: To observe the anesthetic effect of nalbuphine used in ultrasound-guided transvaginal oocyte retrieval and its effect on embryo quality and pregnancy outcome.  METHODS: Four-hundred patients who underwent ultrasound-guided transvaginal oocyte retrieval were randomly divided into two groups (n=200): nalbuphine group (N group) and control group (C group). The patients were in the bladder lithotomy position. Patients in N group were given nalbuphine 0.1 mg/kg intravenously 2 minutes before induction of anesthesia, patients in C group were given normal saline intravenously, and patients in both groups were induced with propofol 1.5 mg/kg. The patients were kept breathing spontaneously, and they were given intravenous injections of propofol (2 mg·kg-1·h-1) and remifentanil (0.1 μg·kg-1·min-1) during the operation to maintain anesthesia. Heart rate (HR), mean arterial pressure (MAP) and pulse oxygen saturation (SpO2) were recorded before anesthesia induction (T0), after anesthesia induction (T1), at time of puncture oocytes (T2), and wake from anesthesia (T3). The operation time, anesthesia recovery time, intraoperative dosage of propofol, dosage of remifentanil and VAS score were recorded. The incidence of respiratory depression, body movement, assisted breathing, postoperative nausea and vomiting and other adverse reactions, as well the satisfaction of doctors and patients after surgery were compared. Embryonic quality and pregnancy outcome related indexes were also recorded. RESULTS: Compared with T0, HR slowed down and MAP and SpO2 decreased at T1, T2 and T3 (P<0.05). Compared with C group, MAP and SpO2 in N group were higher at T1, T2 and T3 (P<0.05), the operation time and anesthesia recovery time were shorter in N group (P<0.05), the dosage of propofol and remifentanil was less (P<0.05), the VAS score 40 min after surgery was lower (P<0.05). Intraoperative respiratory depression, body movement, assisted breathing and postoperative nausea and vomiting were lower (P<0.05), the satisfaction of doctors and patients was higher (P<0.05). There was no significant difference in embryo quality and pregnancy outcome between the two groups (P>0.05). CONCLUSION: 0.1 mg/kg nalbuphine combined with propofol and remifentanil used in ultrasound-guided transvaginal oocyte retrieval patients reveals stable anesthesia process and definite analgesic effect. The satisfaction of doctors and patients is high while the incidence of adverse reactions is low. Also, it does not affect the embryo quality and pregnancy outcome of assisted reproduction patients, which is worthy of clinical promotion and application.
    Clinical study of effect of ezetimibe combined with statins on residual lipoprotein cholesterol and MACE events in patients undergoing emergency intervention with acute coronary syndrome
    DENG Yifan, HE Shenghu, WANG Daxin, DAI Chengye, XU Xiaoting, ZHANG Jing
    2021, 26(9):  1048-1052.  doi:10.12092/j.issn.1009-2501.2021.09.011
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    AIM: To investigate the effect of ezetimibe combined with statins on residual lipoprotein-cholesterol (RLP-C) levels and major cardiovascular adverse events (MACE) in patients with acute coronary syndrome (ACS) after emergency intervention (PCI).  METHODS: A total of 90 hospitalized patients with ACS and undergoing emergency PCI were randomly divided into two groups: 48 patients in the control group received atorvastatin, and 42 patients in the study group were additionally treated with ezetimibe. RLP-C level before and after treatment was detected. The occurrence of MACE events and adverse drug events during the treatment were obtained through regular follow-up. RESULTS: Compared with the control group, the level of RLP-C in the study group was significantly decreased (P<0.05), the incidence of MACE were significantly decreased (P<0.05), and adverse drug events were not increased. CONCLUSION: The combination therapy of ezedemibe and statins can reduce RLP-C level and MACE in ACS patients undergoing emergency PCI with less adverse reactions, which is worthy of promotion and application.
    Research progress and prospect of immunotherapy in the treatment of melanoma
    LI Wei, HU Jiali, WANG Kai, HE Yijing
    2021, 26(9):  1053-1064.  doi:10.12092/j.issn.1009-2501.2021.09.012
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    Cutaneous melanoma is an aggressive and potentially fatal skin cancer which is prone to distant metastasis and spread. Before the advent of targeted therapy and immunotherapy, the prognosis of patients with advanced melanoma is extremely poor, with a 5-year survival rate less than 10%. Compared with traditional treatment, immunotherapy can prolong the progression-free survival and overall survival of patients with advanced melanoma and improve patients' life quality. Although immune-related adverse reactions occur during clinical treatment, most of them could be controlled by giving appropriate immunomodulators. As immunotherapy has received certain attention in clinical, its limitations have also been discovered. Patients have been found to resist or insensitive to immunotherapy, suggesting that the combination therapy may bring greater benefits to clinical treatment. This paper summarized the current the progress and limitations of immunotherapy in clinic for cutaneous melanoma.
    Research progress of α7 nicotinic acetylcholine receptors in central nervous system diseases
    FAN Wenxiang, ZHANG JinLu, XU Chi
    2021, 26(9):  1065-1072.  doi:10.12092/j.issn.1009-2501.2021.09.013
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    Alpha-7 nicotinic acetylcholine receptors (α7 nAChRs) are expressed in the central nervous system (CNS) and are thought to play a role in a wide variety of psychiatric and neurological disorders. Activation of α7 nAChR leads to an anti-inflammatory effect,which may show beneficial effects in those central nervous system disorders. In the present article, we summarize information on receptor distribution and expression, and review the effects of α7 nAChR on the CN disorders (e.g., Alzheimer's disease, Parkinson's disease, and stroke), which may provide a new idea for the development of the treatment of CNS diseases.
    Mesenchymal Stem Cells: a new discovery in the treatment of novel coronavirus pneumonia
    PENG Jing, SONG Jing, LUAN Jiajie
    2021, 26(9):  1073-1079.  doi:10.12092/j.issn.1009-2501.2021.09.014
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    Currently, the corona virus disease 2019 was spreading globally, and more than 167.5 million confirmed cases worldwide. The new corona virus was highly contagious. The human body would have respiratory symptoms, fever, severe respiratory syndrome, organ failure, and even death after being infected with the virus. At present, there was no specific treatment for COVID-19. Most of the treatments were symptomatic and supportive treatment, and the prognosis was poor. Mesenchymal stem cells could not only repair damaged lung tissue, but also regulate immunity and anti-inflammatory effects, and had good clinical application prospects. We will review the application of MSCs in the treatment of COVID-19 for the reference of colleagues.
    Association between mitochondrial oxidative stress and diabetic cardiomyopathy
    WANG Xiaolin, GAO Pan, ZOU Yunzeng
    2021, 26(9):  1080-1085.  doi:10.12092/j.issn.1009-2501.2021.09.015
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    Diabetic cardiomyopathy is described as the existence of abnormal myocardial structure and function caused by diabetes, which is considered to be an underlying cause of increased heart failure in diabetic patients. The pathophysiological mechanisms of diabetic cardiomyopathy are complex and the detailed molecular networks remain obscure. Mitochondrial oxidative stress is the main pathogenic factor of cardiovascular and metabolic diseases, and it is one of the important factors that affect the heart function of diabetes. This review aims to discuss the recent advances of the mechanisms of mitochondrial oxidative stress in diabetic cardiomyopathy, to provide new thoughts for the treatment of diabetic cardiomyopathy.
    Mechanism of CDK1 participates in the development of hepatocellular carcinoma and its inhibitor application value
    YE Kaili, ZHENG Wen, YE Qifa, YANG Lan
    2021, 26(9):  1086-1094.  doi:10.12092/j.issn.1009-2501.2021.09.016
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    Cyclin-dependent kinase 1 is a highly conserved serine/threonine kinase that acts as a checkpoint during mitosis, coordinating and promoting cell cycle progression. CDK1 is significantly upregulated in hepatocellular carcinoma. It is mainly related to p53 signal transduction pathway, LINC00346-miR-199a-3p-CDK1/CyclinB pathway, SNHG16/let-7b-5P/CDC25B/CDK1 pathway and UPF1-SNord52-CDK1 pathway. In this paper, the mechanism of CDK1 involvement in the occurrence and development of hepatocellular carcinoma was systematically elaborated, and the current situation of CDK1 inhibitor targeted treatment of HCC was clarified, which could provide clues and basis for the treatment of HCC with CDK1 as the target.