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

Table of Content

    Volume 28 Issue 3
    26 March 2023
    Silybin ameliorates lipid metabolism disorders in mice with non-alco-holic steatohepatitis
    CAI Zuhuan, DENG Taomei, WEI Naijie, ZHU Dan, QIAN Fei, WANG Guangji, ZHANG Jingwei
    2023, 28(3):  241-248.  doi:10.12092/j.issn.1009-2501.2023.03.001
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    AIM: To investigate the regulatory ef-fects of silybin on hepatic lipid metabolism in mice with non-alcoholic steatohepatitis (NASH) induced by high -fat and high-cholesterol (HFHD) diet. METHODS: Mice were fed a HFHD diet to construct a NASH model, and serum levels of triacylglycerol (TAG), total cholesterol (T-CHO), low-density lipo-protein cholesterol (LDL-C) and high-density lipo-protein cholesterol (HDL-C) were measured using biochemical kits. H&E staining and oil red O stain-ing were used to detect histopathological changes in the liver. Lipidomics was used to detect the alter-ations of hepatic lipid metabolism in NASH mice. 
    RESULTS: Silybin significantly inhibited the increase of body weight, liver weight and abdominal fat, de-creased serum T-CHO,TAG and LDL-C levels, im-proved hepatic lipid droplet accumulation and bal-looning degeneration, and back-regulated hepatic palmitoleic acid (C16:1) and polyunsaturated long-chain fatty acids (PUFAs) in NASH mice. CONCLU-SION: Silybin possibly reduced hepatic lipid accu-mulation and lipotoxicity by modulating abnormal hepatic lipid metabolism in mice induced by HFHC diet. 
    Study on the effect of spinal anesthesia on ventricular arrhythmias in acute myocardial ischemia-reperfusion in rats 
    ZHANG Huabin, LUO Zhongxu, ZHONG Min, HONG Zongyuan, WANG Deguo
    2023, 28(3):  249-256.  doi:10.12092/j.issn.1009-2501.2023.03.002
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    AIM: To explore the effect of spinal anesthesia on ventricular arrhythmia and involved mechanisms in myocardial ischemia-reperfusion (MIR) rats. METHODS: The rat MIR model was made by occlusion the left anterior descending cor-onary artery for 30 minutes and reperfusion for 45 minutes. Bupivacaine (0.05 mL/100 g, 1 mg/kg) was injected slowly via intrathecal for spinal anes-thesia. The electromyelogram at T2 thoracic spinal cord was recorded. Ventricular arrhythmias, cardiac function, myocardial damage were assessed by electrocardiography, echocardiography and TTC or HE staining. RESULTS: MIR reduced left ventricular short-axis shortening (LVFS) and left ventricular ejection fraction (LVEF), caused myocardial histolog-ical damage and ventricular arrhythmias, promoted spinal electrical discharge frequency and amplitude in T2 dorsal horn. Spinal injection of bupivacaine could significantly reduce spinal cord electrical ac-tivities and eliminate MIR-induced arrhythmias. Moreover, bupivacaine also significantly improved MIR-induced myocardial histological damage and cardiac function inhibition. CONCLUSION: Spinal an-esthesia can reduce ventricular arrhythmias in-duced by MIR. The mechanism may be related to the effect of abolishing spinal nerve excitability. 
    Effects and mechanism of dapagliflozin on myocardial injury in type 1 diabetes mice
    ZHANG Xuejiao, LIU Jieting, LI Luxin, CHEN Peijian, DING Minglu, SUN Mengwei, CHU Yanhui, ZHANG Zhen
    2023, 28(3):  257-265.  doi:10.12092/j.issn.1009-2501.2023.03.003
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    AIM: To investigate the effect of dapa-gliflozin on myocardial injury in type 1 diabetes mice and its mechanism. METHODS: Normal C57BL/6J male mice were randomly divided into normal control group (Control), diabetes cardiomy-opathy group (DCM) and dapagliflozin group (DA-PA). The model of diabetes was induced by strepto-zotocin (STZ) and given maintenance feed. DAPA group was given 10 mg ·kg-1·d-1 of dapagliflozin by gavage, while control group and DCM group were given 0.9% sodium chloride solution by gavage. Af-ter 8 weeks of intervention, the cardiac function of each group was measured by ultrasound; Lactate dehydrogenase (LDH) was used to detect myocardi-al injury; HE staining was used to observe the cardi-ac morphology; Masson and Sirius red staining were used to observe the degree of cardiac fibro-sis; TUNEL was used to detect myocardial apopto-sis. The expressions of NLRP3, Caspase-1, GSDMD, Collagen I, Collagen III, α-SMA, Fibronectin, Cas-pase-1 and GSDMD analyzed by immunohistochem-ical staining. The expression levels of NLRP3, Cas-pase-1, GSDMD, Collagen I, Collagen III, α-SMA, Fi-bronectin and IL-18 were detected by Western blot. RESULTS: Compared with the control group, DCM group showed abnormal echocardiographic features, increased serum lactate dehydrogenase, abnormal cardiac tissue structure, disordered ar-rangement of muscle fibers, and obvious fiber thickening and fracture. The staining intensity of apoptosis in myocardial tissue increased, the ex-pression of NLRP3, Caspase-1, GSDMD gene and protein increased, and the expression of Collagen I, Collagen III, α-SMA, fibronectin gene and protein increased. The DAPA group attenuated the previ-ously mentioned parameter changes. CONCLU-SION: Dapagliflozin can improve the degree of myo-cardial fibrosis and myocardial pyroptosis, thus im-proving the myocardial injury caused by diabetes. 
    Exploring the intervention mechanism of Ginkgo biloba for steroid-induced necrosis of the femoral head based on network pharmacology
    CAO Fang, QIN Kairong, ZHENG Guoshuang, ZHAO Dewei
    2023, 28(3):  266-275.  doi:10.12092/j.issn.1009-2501.2023.03.004
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    AIM: To explore the mechanism of Ginkgo biloba in the treatment of steroid-induced osteonecrosis of the femoral head based on net-work pharmacology. METHODS: The active ingredients and targets of Ginkgo biloba were predicted by the TCMSP, ADME, and PharmMapper databases. The disease targets related to steroid-induced osteonecrosis of the femoral head were searched by the GeneCards and OMIM databases. Cytoscape 3.6.1 was used to construct a protein-protein inter-action network. The core target analysis, modular analysis, GO enrichment analysis, and KEGG pathway analysis of the targets of Ginkgo biloba in the intervention of steroid-induced osteonecrosis of the femoral head were performed by the STRING database. RESULTS: In this study, a total of 16 active ingredients of Ginkgo biloba and 547 targets were screened, of which 133 targets were related to steroid-induced femoral head necrosis. By PPI network topology analysis, TP53, AKT1, IL6, VEGFA, MAPK1, JUN, MAPK8, EGFR, EGF, and MYC were identified as the core targets. GO modularization analysis showed that these core targets were mainly related to apoptosis and angiogenesis. GO enrichment analysis was used to analyze the biological processes, cellular localization, and molecular functions of the core targets. KEGG enrichment analysis showed that the targets were mainly involved in molecular signaling pathways, among which the PI3K/AKT signaling pathway was the most relevant. CONCLUSION: Ginkgo biloba can inhibit steroid-induced os-teonecrosis of the femoral head through multiple components, targets, and pathways, which pro-vides the theoretical basis and reference for subse-quent cell and animal experiments.
    Effects of hawthorn flavonoids on atherosclerotic and hyperlipidemia
    LI Junmin, NIU Hengli, XIE Mingquan, SU Jinlong
    2023, 28(3):  276-282.  doi:10.12092/j.issn.1009-2501.2023.03.005
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    AIM: To investigate the preventive and therapeutic effects of Hawthorn flavone on hy-perlipidemia and atherosclerosis rats. METHODS: The atherosclerosis model was established by high fat diet plus vitamin D2. The blood lipid levels, heart index, atherosclerosis index (AI1, AI2) and cor-onary heart index were measured in each group. The histopathological changes of aorta were ob-served by oil red O staining, HE staining and Mas-son staining. ELISA experiments were used to de-tect IL-6, ICAM-1, MCP-1 and VCAM-1 protein level. RESULTS: Compared with normal group, total cho-lesterol (TC), triglyceride (TG), low density lipopro-tein (LDL-C), heart index, atherosclerosis index (AI1, AI2) and coronary index in atherosclerosis model group were significantly increased (P<0.01), while high density lipoprotein cholesterol (HDL-C) was significantly decreased (P<0.01). The pathological score of aorta and the degree of fibrosis were sig-nificantly increased (P<0.01). Compared with model group, TC, TG, LDL-C, heart index, atherosclerosis index (AI1, AI2) and coronary heart index were significantly decreased (P<0.01), and high-density lipo-protein cholesterol (HDL-C) was significantly in-creased (P<0.01) in medium, high dose hawthorn flavonoids and atorvastatin groups. The pathological score of aorta significantly decreased and the degree of fibrosis significantly improved (P<0.01). The variation trend of blood lipid levels in hyperlip-idemia rats is basically consistent with atheroscle-rotic rats. Meanwhile, compared with model group, the medium, high dose hawthorn flavonoids and atorvastatin groups could significantly inhibit the expression levels of IL-6, MCP-1, ICAM-1 and VCAM-1 adhesion molecules (P<0.01). CONCLUSION: The hawthorn flavone can inhibit the forma-tion of aortic endothelial atherosclerotic plaque, re-duce the degree of fibrosis and inflammation of atherosclerotic plaque in rats, and achieve the pur-pose of anti-atherosclerosis. Meanwhile, the haw-thorn flavone has the effect of regulating blood lip-id.
    BSD method for three treatments randomly allocated with equal proportion in clinical trials 
    XU Minyi, LIU Yaqi, LIU Yuxiu, XIONG Yin, GONG Haowen, ZHANG Manting, YU Xihui, ZHAO Yang
    2023, 28(3):  283-289.  doi:10.12092/j.issn.1009-2501.2023.03.006
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    AIM: Previous studies have suggested that big stick design (BSD) method can only be used in clinical trials of two treatments with equal proportion, which has good statistical performance and has become the recommended choice of randomized methods. This study expands BSD meth-od, so that it can be applied to three groups, and provides more randomized methods for clinical trials. METHODS: On the basis of BSD method used in two treatments with equal proportion, the derivation conditional allocation probability of BSD meth-od used in three treatments with equal proportion was carried out. BSD method was compared with simple randomization (SR) method, permuted block design (PBD) method and block urn design (BUD) method by Monte-Carlo simulation in balance and randomness. RESULTS: In terms of balance, PBD method was the best, followed by BUD method, BSD method, and SR method was the worst. In terms of randomness, SR method was the best, followed by BSD method, BUD method and PBD method. The comprehensive performance showed that BSD method was better than BUD method, PBD method and SR method. CONCLUSION: The expanded BSD method used in three treatments with equal proportion has good comprehensive performance, and it can be the recommended randomization method for clinical trials of three treatments with equal proportion.
    Comparison of common parameter estimation methods in NONMEM 7.5.1.: A case study of ibuprofen injection in Chinese healthy adult population 
    LUO Mingjie, LIU Runhan, ZHOU Jie, WANG Zhenlei
    2023, 28(3):  290-298.  doi:10.12092/j.issn.1009-2501.2023.03.007
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    NONMEM. is a software widely used in the field of population pharmacokinetics and pharmacodynamics, mainly for related data analy-sis. In theory, it mainly establishes a parameterized model, combines the obtained data, and uses dif-ferent parameter estimation methods to estimate the parameters in the model, and then analyzes the data according to the model. This paper briefly introduces the representation of parameterized models in NONMEM., and from statistical theory, summarizes three commonly used parameter esti-mation methods under the condition that the ran-domization effect parameters η and .do not inter-act. For nonlinear mixed effects models, the rela-tionships among three parameter estimation meth-ods are given under special cases of addictive intra-individual models and proportional intra-individual models. In addition, through numerical experi-ments on data of four pharmaceutical companies on the change of ibuprofen drug concentration with time, the rationality of theory is further veri-fied in terms of calculation time and model predic-tion residuals. 
    Effects of CDA-G208A gene polymorphism on the efficacy of gem-citabine in the first-line treatment of lung squamous cell carcinoma 
    HE Yang, YANG Kui, LUAN Jiajie
    2023, 28(3):  299-306.  doi:10.12092/j.issn.1009-2501.2023.03.008
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    AIM: To investigate the effect of CDA-G208A gene polymorphism on the efficacy and safety of gemcitabine in the first-line treatment of lung squamous cell carcinoma. METHODS: Sixty-five first-line treated patients with locally advanced or metastatic lung squamous cell carcinoma in The First Affiliated Hospital of Wannan Medical College hospital were screened. Group A included 31 pa-tients tested with the GG (wild homozygous) CDA-G208A gene, and group B included 34 patients without testing. All patients received gemcitabine plus platinum chemotherapy for at least 2 cycles. The efficacy and safety were evaluated following the RECIST 1.1 standard and the NCI-CTC 5.0 stan-dard, respectively. The primary study endpoint was progression-free survival (PFS), overall survival (OS) and the secondary study endpoints included objec-tive effective rate (ORR), disease control rate (DCR), adverse reactions, and influencing factors of PFS. RESULTS: The results showed that the DCR was 74.5% and 50% in group A and group B, respective-ly (P=0.045); mPFS was 6.1 months and 5.0 months in group A and group B, respectively (P=0.034); and the mOS was 13.3 months and 12.0 months in group A and group B, respectively, and there was no statistical difference (P=0.388). The number of cases of grade III-IV neutropenia in group A and group B was 2 and 10, respectively (P=0.017); grade III-IV neutropenia was an independent prog-nostic factor affecting patients with PFS (P=0.045); the group with unknown G208A gene status was more likely to develop grade III-IV neutrophils (P= 0.029). The AUC of CDA-G208A gene predicting neutropenia caused by gemcitabine chemotherapy was 0.756. CONCLUSION: Non-GG type of CDA-G208A gene can reduce the metabolic rate of gem-citabine in the body and cause neutropenia after chemotherapy. In severe cases, it can indirectly re-duce the clinical efficacy of gemcitabine. The detec-tion of CDA-G208A gene status before treatment can predict the neutropenia caused by gemcitabine chemotherapy. 
    Value of red blood cell distribution width in predicting early poor neurologic improvement after intravenous thrombolysis in patients with ischemic stroke 
    WU Zhiyong, LIU Bingrong, LI Bin, TANG Rui
    2023, 28(3):  307-314.  doi:10.12092/j.issn.1009-2501.2023.03.009
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    AIM: To explore the predictive value of red blood cell distribution width (RDW) in early poor neurologic improvement after intravenous thrombolysis in acute ischemic stroke (AIS). METH-ODS: A total of 102 patients with acute ischemic stroke who received intravenous thromblysis with alteplase within 4.5 hours of onset were analyzed retrospectively. RDW level was measured before thrombolysis. According to the percentage change in NIHSS at 24 hours, the patients were divided in-to two groups: good neurological improvement (≥ 30%) group (n=53) and poor neurological improve-ment (<30%) group (n=49). The univariate and mul-tivariate Logistic regression analysis were used to investigate whether RDW level is an independent factor affecting patients' neurological improve-ment. The receiver operating characteristic (ROC) curve was used to analyze the cut-off value of RDW to predict poor early neurological improvement af-ter thrombolysis. RESULTS: Compared with the good neurological improvement group, higher pro-portion of atrial fibrillation (24.5% vs. 9.4%, P=0.042), diabetes mellitus (57.1% vs. 30.2%, P=0.006), hemorrhagic transformation (10.2% vs. 0%, P=0.023) in the poor neurological improvement group. The level of RDW in poor neurological im-provement group was significantly higher than that in good neurological improved group[(14.09±0.77) vs. (13.31±0.63), P=0.000]. Logistic regression anal-ysis showed that elevated RDW (OR=4.614, 95%CI: 2.263-9.408, P=0.000) and history of diabetes melli-tus (OR=2.606, 95%CI: 1.034-6.573, P=0.042) were independently associated with early poor neurolog-ical improvement. The ROC curve analysis showed that the optimal cut-off value of RDW to predict poor early neurological improvement after throm-bolysis was 13.56% (AUC=0.782, 95%CI: 0.690-0.874; sensitivity 76%; specificity 74%). CONCLU-SION: Elevated RDW is of a certain value in predict-ing the poor early neurological improvement of AIS patients after thrombolysis. 
    Application of quantitative pharmacology in vaccine research and de-velopment: overview and prospect 
    MA Guangli, ZHANG Jing
    2023, 28(3):  315-322.  doi:10.12092/j.issn.1009-2501.2023.03.010
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    This article introduces the mechanism including antigen presentation, adjuvant, lymphatic system and the characteristics of vaccine, and then summarizes the key applications of core pharmaco-metrics approaches including QSP, PK/PD, dose re-sponse analysis, MBMA, in dose-response, preclini-cal and clinical translation, and correlation be-tween biomarkers and efficacy of vaccines. It is ex-pected that the successful application of model in-formed drug development can promote model in-formed vaccine development so that pharmaco-metrics makes its due contributions to the develop-ment of safer, more effective and more controlla-ble vaccine products.
    Mechanism of tyrosine kinase 2 inhibitors in treatment of plaque psoriasis and their progress in clinical trials 
    SHEN Jiaqing, LIU Yi
    2023, 28(3):  323-330.  doi:10.12092/j.issn.1009-2501.2023.03.011
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    As a chronic, immune-mediated in-flammatory disease, plaque psoriasis has a great burden of disease and influences on patient's physi-cal and mental health. In the past decade, plaque psoriasis treatment with biological agents achieved breakthrough development, while oral drugs with promising efficacy and safety are yet to be met. By cell signal transduction, the Janus kinase-signal transducer and activator of transcription pathway plays an important role in numerous immune-relat-ed diseases. Tyrosine kinase 2 (TYK2), a member of the JAK family, can impact on plaque psoriasis by regulating signaling and functional responses down-stream of IL-12, IL-23, IFN. Deucravacitinib, a highly selective TYK2 inhibitor, has finished its phase 3 clinical trials and shown its efficacy and safety in treatment of plaque psoriasis. Several kinds of TYK2 inhibitors are under research and develop-ment at the moment. In this review, we demon-strate roles of JAK-STAT pathway and TYK2 in plaque psoriasis as well as updates on ongoing and recently completed trials of TYK2 inhibitors. 
    Research progress of natural plant active ingredients in reversing tumor multidrug resistance by down-regulating P-gp
    LI Shan, LIU Yixin, REN Feifei, LI Xiangchen, ZHANG Zhiqing
    2023, 28(3):  331-340.  doi:10.12092/j.issn.1009-2501.2023.03.012
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    Multidrug resistance (MDR) is the main factor of tumor recurrence and chemothera-py failure in clinical practice. Its mechanism is rela-tively complex, and one of the most thoroughly studied mechanism is the overexpression of P-gly-coprotein (P-gp) on tumor cell membrane. Most of the chemotherapy drugs are p-gp substrates, and tumor cells will transport the chemotherapy drugs to the extracellular through p-gp mediated active transport, so that the concentration of effective drugs in the cell is reduced, resulting in drug resis-tance, leading to the decline of clinical efficacy. The reversal agent of P-gp can reduce the intracellular pumping of chemotherapeutic drugs by regulating the expression and transport activity of P-gp, and enhance the sensitivity of tumor cells to chemo-therapeutic drugs, thus improving the therapeutic effect. In this paper, we will summarize the natural plant active ingredients that can reverse P-gp medi-ated MDR to provide reference for clinical and re-lated studies.
    Research progress on pathogenesis and potential therapeutic target of sarcopenia obesity 
    GUO Yixun, GUAN Xiaoyin, WANG Bo, WEI Yingda, ZHANG Yan, LIN Jianhua
    2023, 28(3):  341-346.  doi:10.12092/j.issn.1009-2501.2023.03.013
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    Sarcopenia obesity (SO), a specific dis-ease with co-occurrence of obesity and sarcopenia, is shown clinically as abnormal accumulation of fat, decreased mass and strength of muscle, and in-creased risk of incidence and mortality of other chronic diseases. Currently, there exist various defi-nitions and diagnoses about SO in the various re-gions of the world. Its prevalence in populations el-evates in an age-dependent manner. This article summarized the possible pathogenesis of SO from the view of chronic inflammation, oxidative stress, insulin resistance, and Hippo pathway, subsequent-ly listed and analyzed potential pharmacological targets (fibroblast growth factor, CD44, adiponec-tin, etc) involved in treating SO, in order to provide new ideas for clinical diagnosis, treatment of SO pa-tients and research and development of innovative drugs.
    Progress on the pathological mechanism and treatment of frostbite 
    ZHANG Li, LIN Xingyao, SHANG Yun, WANG Qiang
    2023, 28(3):  347-354.  doi:10.12092/j.issn.1009-2501.2023.03.014
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    Frostbite is a tissue injury that occurs when the body is exposed to extreme cold. Its path-ological mechanism is complex and has not been ful-ly elucidated. In high cold and high altitude areas, outdoor sports people have a high risk of injury, and severe frostbite has high disability and mortality. Ex-ploring the pathological mechanism of frostbite is helpful to determine the treatment methods and timing. At present, the clinical treatment of frostbite is mainly symptomatic treatment, such as drug treatment and surgical treatment, but the curative effect can not meet the clinical needs. Therefore, it is of great significance to seek more efficient drugs or treatment methods. This article reviews the rele-vant research progress in pathophysiological mecha-nism, clinical treatment, cellular and molecular path-ways of frostbite in recent years, in order to provide new ideas for future research and clinical treatment. 
    PDE4 inhibitors serve as therapeutic targets for pulmonary fibrosis 
    LIU Nanyu, YUE Hongmei, SONG Peipei, WEI Jifang, WEI Yaqian, XIE Yingying, WANG Jiaqi
    2023, 28(3):  355-360.  doi:10.12092/j.issn.1009-2501.2023.03.015
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    Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal chronic interstitial lung disease characterized by a progressive decline in lung function, and current treatment options are limited. cAMP is one of the most important second messengers and plays a key role in relaxing airway smooth muscle cells and reducing inflammation. Phosphodiesterase (PDE) is a superfamily of enzymes, and PDE4 enzymes dominate 11 PDE super-family enzymes, available in four isoforms-PDE4A, PDE4B, PDE4C and PDE4D, which selectively decompose cAMP, while PDE4 inhibitors increase cAMP levels by preventing cAMP from breaking down, thereby exerting anti-inflammatory, anti-remodeling effects and providing an attractive drug target for the treatment of IPF. This review summarizes knowledge about the association of pulmonary fibrosis with PKE4, as well as emerging preclin-ical studies and clinical trials regarding PDE4 inhibitors.