Table of Content

Volume 23 Issue 9
26 September 2018

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The value and general consideration of pharmacometric study in new drug development

LIU Dongyang,WANG Kun,MA Guangli,XIANG Xiaoqiang,LIU Jiang,ZHAO Ping,CHEN Rui,CHEN Yuancheng,HUANG Xiaohui, LI Li,LI Lujin,NIE Jing,WANG Yuzhu,WEI Chunmin,LU Wei,SHI Jun, ZHENG Qingshan

2018, 23(9):  961-973.  doi:10.12092/j.issn.1009-2501.2018.09.001

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Pharmacometrics is a discipline to quantitatively investigate information, such as pharmacokinetics, pharmacodynamics, physiology, disease progression, and clinical trial, to produce knowledge using modeling and simulation methods. It supports new drug development since early phase in a life cycle, which forms a model-informed drug development mode to improve efficiency of drug development and regulatory administration, save development costs, and accelerate approval of new drug.This article illustrates the values and investigates the properties, application assumptions, and standard operation procedures of pharmacometrics during new drug development based on consensus of experts in domestic and overseas. We hope this white paper could standardize and improve the application of pharmacometrics in new drug development in China. 

Protective effects of Cordyceps sinensis powder on liver injury induced by DEN in rats and the effect of TGF-β1/Smads pathway

HE Yang, SONG Liying, PENG Xiangdong, FANG Weijin, WANG Chunjiang, DENG Zhenzhen, LIU Shikun

2018, 23(9):  974-982.  doi:10.12092/j.issn.1009-2501.2018.09.002

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AIM: To investigate the protective effects of fermented Cordyceps Sinensis powder (CS) on Diethylnitro-samine (DEN) induced liver injury in rats and its effect on TGF-β1/Smads pathway. METHODS: Forty-eight male SD rats［SPF, weighing (180±20) g］ were randomly divided into four groups (12 rats in each group): control group, model group, CS treatment group and CS solvent group; model group were gavaged with DEN (10 mg/kg), 5 times a week for 8 weeks to build a model of chronic liver injury; control group were gavaged with saline with the same volume of the model group; CS treatment group: after 4 weeks of modeling, CS treatment group were gavaged with CS (80 mg/kg), 5 times a week for 8 weeks; CS solvent group were gavaged with 5% sodium carboxymethyl cellulose solution (CMC-Na) with the same volume of the CS group. At the end of the experiment, the rats were sacrificed by spinal dislocation, blood was collected, and the serum AST and ALT were detected by UV spectrophotometry to reflect the liver function; H&E staining was used to observe the morphological changes of liver tissue; Masson staining was used to observe collagen deposition; primary hepatic stellate cells (HSCs) were isolated by modified Nycodenz method; the expression of α-SMA, TGF-β1, Smad3 and Smad7 mRNA in liver tissue and HSC were detected by RT-qPCR; expression of Smad3 and Smad7 protein in liver tissue were detected by Western blot. RESULTS:Compared with the control group, the levels of AST and ALT in the serum of the model group were significantly increased, the morphology of the liver was significantly changed by H&E staining, and Masson staining showed that collagen deposition increased; compared with the model group, CS treatment could significantly reduce serum AST and ALT levels, improve liver pathological damage and reduce collagen deposition in the liver. RT-qPCR results showed that CS could reduce the expression of α-SMA, TGF-β1, Smad3 mRNA and increase expression of Smad7 mRNA in liver tissue and HSC of rats with liver injury. In addition, Western blot results showed that CS could reduce the expression of Smad3 protein and increase Smad7 expression in the liver tissue of rats with liver injury. CONCLUSION:CS can significantly improve DEN induced hepatic injury in rats, which may be related to the up-regulation of Smad7 by CS and the inhibition of TGF-β1/Smads pathway.

Absorption mechanism of a novel tubulin inhibitor,YMR-65, in Caco-2 cell model

FAN Ali, XUE Siqi, WEI Jiali, LI Ning, ZHAO Di, LU Yang, CHEN Xijing

2018, 23(9):  983-988.  doi:10.12092/j.issn.1009-2501.2018.09.003

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AIM: To study the uptake and transport characteristics of a novel tubulin inhibitor, YMR-65, in Caco-2 cells model and to provide ideas and methods for new drug development. METHODS: By establishing Caco-2 cell model, the effects of time, concentration and temperature on the uptake of YMR-65 were studied using intracellular uptake amount. Time, concentration or verapamil on its transport in Caco-2 cells were evaluated using apparent permeability coefficient (Papp). RESULTS:In Caco-2 uptake model, the cumulative amount of YMR-65 in Caco-2 cells increased in time- and concentration- manners without obvious saturation and it seemed that the uptake characteristics was unaffected by temperature. Time, concentrations or P-gp inhibitor showed no significant difference to the apparent permeability coefficient (Papp) in Caco-2 cells. CONCLUSION: YMR-65 is passively diffused into Caco-2 cells and it suggests that P-gp might not be involved in the intracellular transport of YMR-65 and it might not be the substrate of P-gp.

Evaluation of effects of Chinese medicine Sailuotong on metabolic enzymes in rats by cocktail probe method

2018, 23(9):  989-997.  doi:10.12092/j.issn.1009-2501.2018.09.004

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AIM: To prevent drug interactions induced by the combination of drugs, the effects of Sailuotong, a traditional Chinese medicine compound used to treat vascular dementia, on main drug metabolic enzymes in rats were investigated.  METHODS: After intragastric administration, the rats were given Sailuotong, and extract of ginseng, ginkgo leaf and crocus. They were then given cocktail of CYP1A2 (caffeine), CYP2C (omeprazole and losartan), CYP2D2 (dextromethorphan) and CYP1A1/2 (midazolam) probes. The blood drug concentration of each probe and specific metabolic substrate at different time points after administration was measured. The effects of single dose Sailuotong on the main CYP450 activity of rats were evaluated by analyzing the pharmacokinetic parameters and metabolic rate of the probe drug and its metabolite (the ratio of the metabolite to the probe AUC). RESULTS: Compared with the blank control, no statistically significant changes in the metabolic rate of each probe were found after single administration of Sailuotong (P>0.05). The peak time of caffeine probe drug was significantly delayed, while the peak concentration of metabolites was significantly increased, and the metabolic rate was increased by 31%, which was consistent with the trend after administrating ginseng extract. The AUC value of dextromethorphan metabolite was significantly decreased by single dose Sailuotong, while the metabolic rate was decreased by 37%, which was mainly induced by ginkgo leaf extract. CONCLUSION: Main metabolic activity of CYP450s in rats was not significantly affected by single dose of Sailuotong. The whole change trend was consistent with the combined effect of compound prescription.

TIM4 expression of dendritic cells and inflammation effects in OVA-induced asthma model treated with lentinan

CHEN Ye, HE Shoudi, HU Zhili, FENG Bin

2018, 23(9):  998-1002.  doi:10.12092/j.issn.1009-2501.2018.09.005

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AIM: To study the expression of TIM4 in dendritic cells and the effect of inflammation in OVA-induced asthma model mice treated with lentinan. METHODS: Balbc female mice were randomly divided into three groups: normal control group, asthma model group, lentinan treatment group. The asthma model was induced by OVA in mice. In the treatment group, lentinan was injected intraperitoneally every day from the 7th day, and the asthma model group was injected intraperitoneally with physiological saline instead of lentinan. The expression of TIM4 in dendritic cells was detected by flow cytometry in mononuclear cells from spleen. ELISA was used to detect the concentration of MCP-1 and IL-4 in the serum. Q-PCR was used to detect the expression of TIM4 in lung tissue and HE staining for lung. RESULTS: After treatment, lentinan could down-regulate the expression of TIM4 in dendritic cells from spleen (P<0.05), decrease the concentration of IL-4 and MCP-1in the serum (P<0.05, P<0.01). The expression of TIM4 RNA in lung tissue was decreased (P<0.05). HE staining showed that the inflammation of the lung tissue in the treatment group was significantly reduced. CONCLUSION: Lentinan can inhibit the expression of TIM4 in dendritic cells, reduce the concentrations of inflammatory cytokines such as IL-4 and MCP-1, and inhibit the inflammatory response in OVA-induced asthma model.

Experimental study on the effect of total flavonoids of Pueraria lobata on inflammatory cytokines in rats with inner ear injury induced by isoproterenol

ZHAO Jiangtao, LIANG Yange

2018, 23(9):  1003-1007.  doi:10.12092/j.issn.1009-2501.2018.09.006

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AIM: To investigate the effect of total flavonoids of Pueraria lobata on inflammatory factors after isoprenaline induced inner ear injury in rats. METHODS: The rats were divided into four groups: the high and low dose group of total flavonoids of Pueraria lobata, the model group and the negative group. The changes of TNF-α, IL-4, ACTH and Bax protein in rats with inner ear injury induced by isoproterenol were observed and compared.RESULTS:Compared with the negative group, the serum TNF-α, IL-4, ACTHX, Bax content in the administration group and the model group was significantly higher than that in the model group (P＜0.05), and was significantly higher than those in the model group (P<0.05). The content of TNF- α, IL-4, Bax in serum decreased (P<0.05) and the content of ACTH increased in the treatment group (P<0.05), especially in the high-dose group compared with the low-dose group (P<0.01). CONCLUSION: Total flavonoids of Pueraria lobata can effectively inhibit the release of TNF-α, IL-4 inflammatory factor and regulate the expression of ACTH, Bax protein in rat inner ear injury induced by isoprenaline.

YAP gene silencing to improve the drug sensitivity of imatinib resistant myeloid leukemia cells K562

WANG Jin, YANG Yi, GUAN Qiaobin, CHEN Qixu, GUO Li, HAN Chenyang

2018, 23(9):  1008-1014.  doi:10.12092/j.issn.1009-2501.2018.09.007

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AIM: To explore the effect and mechanism of enhanced imatinib resistant K562 cells (K563/IMA) on imatinib sensitivity after YAP gene silencing, and to support the treatment of imatinib resistant myeloid leukemia. METHODS: Transfection of YAP gene silencing with siRNA-YAP was conducted by small interference RNA technique (siRNA) in K562/IMA. The control group (control), the siRNA negative control group (siRNA-NC) and the YAP siRNA group (siRNA-YAP) were established. The expression level of YAP protein and mRNA in each cell after silencing was identified by RT-QPCR and Western blot. The sensitivity of each cell to imatinib was detected by CCK-8, and the median inhibitory concentration of IC50 was calculated. Flow cytometry was used to detect the apoptosis rate of each group. The expression level of YAP, Bcl-2, Bax, cleaved-caspase3, caspase-3 and Cyto-C were detected by Western blot. The metastasis and invasion were detected by Transwell compartment. RESULTS: After the YAP gene silenced, the expression level of YAP protein and mRNA in the siRNA-YAP was significantly lower than that in the control and the siRNA-NC. The IC50 value of siRNA-YAP was significantly lower than that of control and siRNA-NC, which was statistically significant (P<0.05). The results of flow cytometry showed that the apoptotic rate of siRNA-YAP was significantly higher than that of control and siRNA-NC at the same dosage, which was statistically significance (P<0.05). The migration and invasiveness of K562/IMA cells in YAP silenced were decreased significantly. After imatinib intervene, the level of Bcl-2/Bax in siRNA-YAP cells was down-regulated, and the levels of cleaved-caspase3, caspase-3 and Cyto-C were up-regulated. Compared with control and siRNA-NC, it was statistically significant (P<0.05). CONCLUSION: To silence the YAP gene in imatinib resistant K562/IMA cells can restore the sensitivity of tumor cells to imatinib, and promote the activation of mitochondrial apoptotic pathway, resulting in the apoptosis of drug-resistant tumor cells.

Effects of nicotinamide ribose on adolescent depression rats after neonatal maternal deprivation

WANG Rouxin, FANG Zekang, YAO Siqi, XUE Yingying, ZHAO Yeying, YE Yilu

2018, 23(9):  1015-1021.  doi:10.12092/j.issn.1009-2501.2018.09.008

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AIM: To explore the effects of nicotinamide ribose (NR) on adolescent depression rats after neonatal maternal deprivation (NMD). METHODS: NMD was performed as mother-infant separation from postnatal day (PND) 2 to PND 21 for 3 hours (9∶00-12∶00 AM) each day. At PND 21, isolated rats were divided into three groups randomly: isolated depression group (saline, n=6), sertraline group (40 mg·kg^-1·d^-1, n=7) and NR group (400 mg·kg^-1·d^-1, n=7), which were treated for 21 days and once daily. The normal control rats were treated with saline (n=6). From PND 42 on, forced swimming test (FST), sucrose preference test (SPT), open field test (OFT) and novel object recognition test (NORT) were detected. Then the contents of 5-HT, DA, NE and NAD⁺ in the hippocampus and prefrontal cortex (PFC) were detected by respective ELISA kits. RESULTS: Exposed to NMD, the body weight increased slightly. NR treatment had no improvement on body weight compared with normal control group. However, NR treatment increased the sucrose preference ratio, rearing times, discrimination ratio (DR) and discrimination index (DI). Also NR treatment decreased the immobility time in FST. The results of ELISA showed NR treatment increased the contents of DA, NE, NAD⁺ in the frontal cortex and the contents of DA, NAD⁺ in hippocampus. CONCLUSION: NR improved the depressive behaviors through the increase of neurotransmitters contents and NAD⁺ . It maybe provide experimental basis for screening of anti-depressants.

Chrysin attenuates oxidative stress in human umbilical vein endothelial cells

GAO Xuemei, ZHANG Xiali, CHEN Min, LI jie, LUO Le, HAN Sijia, DONG ji, SONG Zhenrong, ZHANG Xuanping

2018, 23(9):  1022-1026.  doi:10.12092/j.issn.1009-2501.2018.09.009

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AIM: To observe the protective effects of chrysin against H2O2-induced oxidative stress injury in human umbilical vein endothelial cells (HUVECs) and the possible mechanism. METHODS: HUVECs were subjected to H2O2 in the absence or presence of chrysin (25, 50, 100 μmol/L) for 2 h. The 3-(4,5-Dimethylthiazol-2-yl l)-2,5 -diphenyltetrazolium bromide (MTT) assay was used to assess cell viability. Reactive oxygen species was detected by dichlorofluorescein diacetate (DCFH-DA). The release of lactate dehydrogenase (LDH), the level of malondialdehyde (MDA), NO, superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS) in culture media or in cells were assessed using commercial kit according to the manufacturer's instructions. The expressions of adhesion molecule mRNA were detected by reverse transcription-quantitative polymerase chain reaction. RESULTS:The results showed that H2O2 increased the release of LDH, the production of MDA and ROS, the mRNA level of adhesion molecules, decreased the cell viability and the activity of SOD and eNOS, reduced the production of NO. Pretreating HUVECs with chrysin improved cell viability and inhibited the release of LDH, reduced the production of ROS and MDA, alleviated the mRNA level of adhesion molecules, elevated the production of NO, improved the activity of SOD and eNOS. CONCLUSION: Chrysin might exert protective effects against oxidative stress in HUVEC.

Inhibitory effect of cisplatin combined with zoledronic acid on the cell proliferation of lung cancer

QIN Boyu, WANG Gang, QI Xiaoguang, WANG Yajie, SUN Qiong, SUN Shengjie

2018, 23(9):  1027-1030.  doi:10.12092/j.issn.1009-2501.2018.09.010

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AIM: To investigate the inhibitory effect of cisplatin combined with zoledronic acid on lung cancer cell PLA-801D proliferation. METHODS: Cell growth inhibitory rate of cisplatin combined with zoledronic acid was determined with MTT assay. The cell cycle was detected by flow cytometry. RESULTS: Cell proliferation was inhibited under the treatment of cisplatin, zoledronic acid alone. The inhibitory rate showed a dose dependent effect within a certain drug concentration range. Compared with single-drug treatment, the combined treatment of cisplatin and zoledronic acid showed a synergistic effect on cell growth inhibition. The highest inhibitory rate was found in sequential cisplatin+zoledronic acid group (cells were first incubated with cisplatin followed by zoledronic acid treatment 24 h later). In addition, compared with the control group, the S phase was longer after combined treatment of cisplatin and zoledronic acid. CONCLUSION: Sequential treatment of cisplatin and zoledronic acid show the strongest inhibitory effect on the cell proliferation of lung cancer. The ranged inhibitory effect may be related with the change of cell cycle.

Dose selection of indacaterol for marketing approval: a FDA story in pharmacometrics review

YIN Fang, WANG Yuzhu, ZHENG Qingshan

2018, 23(9):  1031-1039.  doi:10.12092/j.issn.1009-2501.2018.09.011

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The safety of long-acting β2 agonist (LABA) has always been controversial, and the dose selection of this type of drugs becomes very important issue. Pharmacometrics is a key evaluation tool for the dose selection. In the process of review of indacaterol for marketing approval by US FDA, the pharmacometric scientists from FDA and an enterprise, respectively conduct modeling & simulation based the data from the same trials, and they found different doses for marketing with refuting each other and debating in academic journals, even the journal published the commentary. Apparently, FDA's model is more persuasive. This is an excellent case of pharmacometrics in the new drug review of dose for marketing, which fully demonstrates the advantages of pharmacometrics, that is, when the head-to-head study is lacking, many trial data are integrated, and the final marketing dose is determined by modeling and simulation. At the same time, pharmacometric characteristics, such as multidisciplinary, highly professional, complex analytical process and the requirements of experience, are also showed. Be boldly hypothesized but must be carefully verified.

Efficacy and safety analysis of fiberoptic bronchoscopy combined with methylprednisolone in children with RMPP

LV Xiaojuan, TANG Weihong, WANG Huiting, WANG Zhongmin, GUAN Minchang, LI Haifeng

2018, 23(9):  1040-1046.  doi:10.12092/j.issn.1009-2501.2018.09.012

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AIM: To explore the efficacy and safety of fiberoptic bronchoscopy combined with methylprednisolone in children with refractory mycoplasma pneumoniae pneumonia (RMPP) and the role of sB7-H3 in RMPP.  METHODS: Seventy cases of RMPP (from July 2015 to October 2017) in our hospital were divided into bronchoscope group (n=35) and combined treatment group (n=35) according to random number table method. The bronchoscope group accepted the conventional treatment for three days, and then accepted the treatment of fiberoptic bronchoscopy for alveolar lavage. The combined treatment group accepted the conventional treatment and methylprednisolone for three days, and then accepted the fiberoptic bronchoscopy for alveolar lavage. And 35 patients with bronchoscopy due to foreign bodies in the same period were chosen as normal control group. After the treatment for 4 weeks, the total effective rates, disappearance time of cough, disappearance of fever, disappearance of rales, normal time of chest radiograph, complications and adverse reactions were observed. And the levels of sB7-H3 and other inflammatory factors in bronchoalveolar lavage fluid of two groups and normal control were observed. The relationship between sB7-H3 and inflammatory factors in RMPP patients were analyzed. RESULTS:After the treatment for four weeks, the total effective rate of combined treatment group (97.1%) was much higher than that of bronchoscope group (82.9%), which was significantly different (P<0.05). The disappearance time of cough, fever, rales, normal time of chest radiograph in combined treatment group were much shorter than these in bronchoscope group (P<0.05). The levels of sB7-H3, IL-1β, IL-2, IL-6 and INF-γ in RMPP patients were much higher than those of normal control group (P<0.05). And the levels of sB7-H3, IL-1β and IL-2 in combined treatment group were much lower than those in bronchoscope group (P<0.05). Among the RMPP patients, there were positive correlations between sB7-H3 with IL-1β (r=0.815, P<0.001) and IL-2 (r=0.629, P<0.001), while there were no correlations between sB7-H3 with IL-6 (r=0.295, P=0.165) and INF-γ (r=0.189, P=0.148). There were no serious complications and adverse drug reactions in both groups. CONCLUSION: The effect of fiberoptic bronchoscopy combined with methylprednisolone in RMPP children is significant; it can significantly shorten the course of the disease. Furthermore, the levels of sB7-H3, IL-1β, IL-2, IL-6 and INF-γ in RMPP children were significantly increased, and the combined treatment may reduce the levels of sB7-H3, IL-1β and IL-2. In addition, sB7-H3 may be involved in the release of IL-1β and IL-2, thereby promoting the occurrence of RMPP.

Effects of medicated bath hydrotherapy combined with Yinzhihuang oral liquid on neonatal jaundice

LI Yongpei, ZHU Yunxia, HUANG Ting

2018, 23(9):  1047-1051.  doi:10.12092/j.issn.1009-2501.2018.09.013

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AIM: To observe the therapeutic effect of medicated bath hydrotherapy combined with Yinzhihuang oral liquid on neonatal jaundice. METHODS: A total of 392 neonates with jaundice were selected from March 2016 to January 2018 in our hospital, which were randomly divided into hydrotherapy group and shower group, each with 196 cases. Both groups took Yinzhihuang oral liquid. The hydrotherapy group was supplemented with medicated bath hydrotherapy, and the shower group was given routine shower. The following indexes, including jaundice index, jaundice regression time, weight change, TBIL, ALT, TBA, CRP, IL-6, IL-8, IgA, IgG and IgM levels, and changes in red cell immune function were compared between these two groups. RESULTS:After treatment, the jaundice index of the medicated bath hydrotherapy group was lower than that of the shower group, and the regression time of the jaundice was significantly shorter, while the weight of the children after treatment was higher than that of the shower group with significant differences (P<0.05). After treatment, serum levels of TBIL, ALT, and TBA in the medicated bath hydrotherapy group were lower than those in the shower group, and the difference was statistically significant (P<0.05). The levels of serum CRP, IL-6, and IL-8 in the Chinese medicine hydrotherapy group were lower than those in the shower group, and the difference was significant (P<0.05). The plasma levels of IgA, IgG, IgM, and RBC-C3bR in the medicated bath hydrotherapy group were significantly higher than those in the shower group. The difference was statistically significant (P<0.05). CONCLUSION: The treatment of Yinzhihuang oral liquid supplemented with medicated bath hydrotherapy can effectively improve the neonatal jaundice and contribute to the improvement of children's immunity.

A randomized controlled clinical trial of azithromycin combined with methylprednisolone in treating pulmonary consolidation from mycoplasma pneumonia

ZHANG Wenxi, LIU Donghong, ZHAO Bei, ZHAO Jiajia, CAI Qiao, GAO Wei, CAI Benben

2018, 23(9):  1052-1055.  doi:10.12092/j.issn.1009-2501.2018.09.014

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AIM: To explore the clinical effect of azithromycin combined with methylprednisolone in treating pulmonary consolidation from mycoplasma pneumonia. METHODS: Eighty-two patients with pulmonary consolidation from mycoplasma pneumonia were divided into control group and treatment group according to random number table method. The control group received routine treatment combined with azithromycin of 10 mg·kg^-1·d^-1 (intravenous drip,qd) and for a continuous treatment of 5 days. The treatment group received extra methylprednisolone of 1 mg/kg (intravenous drip,q12h) for a continuous treatment of 5 days on the basis of the control group. The clinical efficacy,clinical symptom relief time, the serum index and the adverse reaction occurred between two groups were compared. RESULTS: After treatment, the total effective rate in the treatment group and the control group was 90.24%(37/41) and 70.73%(29/41), respectively (P<0.05). The clinical symptom relief time in the treatment group was shorter than that of the control group (P<0.05). The C reactive protein (CRP) in the treatment group and the control group was (14.73±1.84) and (19.64±2.63)mg/L, interleukin-6 (IL-6) was (50.49±6.05) and (69.21±7.42) mg/L, erythrocyte sedimentation rate (ESR) was (27.47±3.30) and (31.11±4.73) mm/h,respectively (P<0.05). Both groups had rashes and itching, nausea and vomiting, and the adverse reaction rate in the treatment group and the control group was 26.83% (11/41) and 12.19% (5/41), respectively (P>0.05). CONCLUSION: The combined treatment of azithromycin plus methylprednisolone for pulmonary consolidation from mycoplasma pneumonia is better than azithromycin alone.It can effectively relieve clinical symptoms and improve clinical effect with no significant increase in the incidence of adverse drug reactions.

Analysis and treatment of adverse reactions associated with four gadolinium contrast agents

WANG Junda, LENG Jing, YANG yalin, LI Yanyan

2018, 23(9):  1056-1062.  doi:10.12092/j.issn.1009-2501.2018.09.015

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AIM: To discuss the factors related to the adverse reaction (ADR) in the clinical application of four gadolinium contrast agents and the best way to deal with it. METHODS: The characteristics of the contrast agent, the patient's constitution, the diagnosis and treatment, the application of contrast agent, the history of pre-enhanced basic medication and the occurrence of ADR (gadolinium contrast agent osmotic pressure, the form of the blood in the blood after the injection, the way of excretion, the patient's age, sex, dosage, injection, enhancement time, enhanced site; ADR reaction time, severity, treatment after treatment) were compared to comprehensively analyze the contrast agent adverse reaction factors, summary of contrast agent induced acute, late onset and ultra late onset ADR incidence, occurrence characteristics and corresponding clinical treatment methods. RESULTS: Age, injection velocity, pre- enhanced base medication and scanning site were independent risk factors for gadolinium contrast agent ADR; linear ionic specific agent had the highest ADR; the symptoms of various systems and different levels of ADR were strictly symptomatic; all the systems were most common with acute skin symptoms, without special treatment, high recovery rate, late onset or super. Late onset patients need to be treated with antihistamine or glucocorticoid, and no gadolinium deposits of NSF, dentate nucleus, double lung, and pleura were found in patients who had been enhanced with a number of large dose contrast agents within 4 years of follow-up. CONCLUSION: The relative incidence of ring-shaped contrast agents show less ADR, and the history of basic medication (diabetes, allergic rhinitis, tumor History) before the enhancement, and the middle-aged outpatient with large dose of slow weight and light weight when the enhancement is enhanced, have the highest acute mild ADR. The medical workers in the imaging department should master the reasonable ADR treatment, which can effectively reduce the incidence of adverse reactions.

Research progress on the population pharmacokinetics of voriconazole and its application in the design of dosage regimen

DAI Ying, ZHANG Haina, LIN Guanyang, YU Xuben

2018, 23(9):  1063-1067.  doi:10.12092/j.issn.1009-2501.2018.09.016

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Voriconazole is widely used as the first-line treatment for invasive fungal infections, but its therapeutic window is narrow, and inter-individual and intra-individual variability in voriconazole pharmacokinetic properties is high. Here, we analyzed the domestic and foreign literatures on the population pharmacokinetics of voriconazole and summarized the population pharmacokinetic characteristics of voriconazole in patients with invasive fungal infections, transplant patients or immunodeficiency patients, and the application in the design of dosage regimen, to improve drug treatment efficiency, reduce the occurrence of adverse reactions, thereby providing theoretical basis for clinically individualized voriconazole administration.

Research progress of miR-423-5p, TFFs and NAG-1 in anti NASIDs induced gastric mucosal injury

LI Xiaomei, LI Xiaoqin, HE Haibo, ZHANG Yongfeng, XU Haiyan, QIN Huilin, ZHANG Jihong, WANG Junzhi, LUO Tao

2018, 23(9):  1068-1074.  doi:10.12092/j.issn.1009-2501.2018.09.017

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of antipyretic and analgesic drugs widely used in clinic. However, gastric mucosal injury caused by NSAIDs is also common. To clarify the pathogenesis of gastrointestinal mucosal injury induced by NSAIDs, and to find new anti-inflammatory drugs with good anti-inflammatory effect and few side effects of gastric mucosal injury are the research hotspots of many medical workers. In recent years, researches at home and abroad have shown that microRNA423-5p, TFFs and NAG-1 are involved in the process of gastric mucosal injury, but the relationship among the aforementioned three is still unclear. This article reviews the mechanism of gastric mucosal injury induced by NASIDs, their properties and their interaction in gastric mucosal injury.

Research progress of IL33/ST2 in acute coronary syndrome

ZHANG Qian, FU Hong, CHEN Jinjin, ZHU Yubing

2018, 23(9):  1075-1080.  doi:10.12092/j.issn.1009-2501.2018.09.018

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The interleukin-33 (IL-33), which is a new member of the Interleukin-1(IL-1) immunoglobulin family, binds to the target cell membrane growth-stimulating expression gene 2 (ST2) to form a trans membrane complex. The IL-33/ST2 signaling pathway is involved in many inflammatory and immune diseases with the activation of Th2. In recent years, many studies have reported that IL-33/ST2 signaling pathway also plays an important role in cardio- and cerebro-vascular diseases such as coronary heart disease. Acute coronary syndrome (ACS) is a serious type of coronary heart disease based on the process of plaque rupture and erosion following the inflammatory lesions of coronary artery. This article aims to provide a new target and idea for the treatment of acute coronary syndrome by reviewing the progress of the studies of IL-33/ST2 signaling in acute coronary syndrome.