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Table of Content

    28 February 2021, Volume 30 Issue 2
    Review
    Significance of neutralizing antibodies in COVID-19 therapy: progress and prospect
    Zeqi Zhou, Xiangbin Wang, Xiqing Zhang, Yuan Zhang, Yankai Fu, Zhixian Wang, Yan Su, He Wang, Meng Xiao, Changxiao Liu
    2021, 30(2):  87-106.  DOI: 10.5246/jcps.2021.02.008
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    SARS-CoV-2 infection is a serious threat to human life and health all over the world, and COVID-19 is a global epidemic caused by SARS-CoV-2 infection. SARS-CoV-2 is highly infectious, strange and variable. Therefore, the treatment of COVID-19 must be urgent and targeted. However, vaccines and currently used drugs generally do not have the above-mentioned characteristics. Although convalescent plasma of COVID-19 has shown a clinical application value in the emergency treatment of critical patients, it shows great limitations. All human recombinant multivalent neutralizing nano-antibodies may meet the deficiency of COVID-19 therapy. Gene engineering technologies have been used to develop specific neutralizing antibody (nAB) drugs for the treatment of COVID-19 worldwide. Some of the candidate nAB drugs have been entered the clinical trials and can be used for the therapy of COVID-19 shortly. In the present review, we studied and analyzed nABs for the treatment of COVID-19 and the progress and prospect from the following five aspects: 1) The biological and clinical characteristics of SARS-CoV-2 infection; 2) The feasibility of plasma therapy for convalescents with COVID-19; 3) The technical routes of developing nAb drugs; 4) The current status of developing global COVID-19 antibodies; 5) The difficulties and clinical use.

    Original articles
    Proteomic analysis on cellular response induced by nanoparticles reveals the nano-trafficking pathway through epithelium
    Jian Zhang, Mengmeng Qin, Dan Yang, Wenbing Dai, Hua Zhang, Xueqing Wang, Bing He, Qiang Zhang
    2021, 30(2):  107-118.  DOI: 10.5246/jcps.2021.02.009
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    The application of nanomedicines in oral drug delivery effectively promotes the drug absorption and transportation through enterocytes. Nevertheless, the absence of mechanism studies on efficacy and safety limits their final translation in humans. Although the vesicular trafficking has been verified as the general character for transport of nanomedicines, the deeper mechanism in molecular mechanism is still unclear. Moreover, the cellular transport of nanomedicines is a dynamic process involved by different organelles and components. However, most of existing studies just pay attention to the static location of nanomedicines, but neglect the dynamic biological effects on cells caused by them. Here, we prepared gold nanoparticles (AuNPs) as the model and cultured epithelial cell monolayer to explore the nano-bio interactions at the molecular level. The traditional pharmacological inhibition strategy and subcellular imaging technology elucidated the macropinocytosis/endosome/MVB/lysosome pathway during the transportation of AuNPs. Proteomics strategy based on mass spectrometry (MS) was utilized to identify and quantify proteins involved in the cellular transport of nanomedicines. Multiple proteins related to subcellular structure, signal transduction, energy transformation and metabolism regulation were demonstrated to be regulated by nanoparticle transport. These alterations of protein expression clarified the effects of intracellular proteins and verified the conventional findings. More importantly, it revealed a feedback mechanism of cells to the nano-trafficking. We believed that these new regulatory mechanisms provided new insights into the efficient transport of nanomedicines through epithelial barriers.

    A PK/PD model of saxagliptin: to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function
    Lu Shi, Feng Miao, Guopeng Wang, Wenyan Sun, Yang Liu
    2021, 30(2):  119-132.  DOI: 10.5246/jcps.2021.02.010
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    In this study, we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK)/pharmacodynamic (PD) model for saxagliptin, simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment, and provide a new method for the research to the clinical pharmacy of special patients. Based on the drug-specific properties, such as logD, plasma protein binding collected by the published literature, the WB-PBPK model and the PD model were established. After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation, the WB-PBPK model could be optimized. After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects, the PD model could be optimized. The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment. All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects (Cmax and AUC were less than 1.3-fold). The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization, and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully. The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.

    Analysis of the effect of HCV resistance-associated substitutions on the short-term efficacy of DAA after single administration in three phase Ib clinical trials
    Jing Zhou, Hong Zhang, Xiaojiao Li, Xiangshi Song, Mengmeng Zhang, Yanhua Ding
    2021, 30(2):  133-145.  DOI: 10.5246/jcps.2021.02.011
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    As crucial factors in hepatitis C virus (HCV) management, resistance-associated substitutions (RASs) are associated with the treatment outcome of some direct-acting antiviral (DAA)-based regimens. In this study, we mainly analyzed the impact of baseline Y93H or Y93Y/H on the short-term efficacy after single administration of NS5A inhibitors in three phase Ib clinical trials (yimitasvir phosphate, KW-136 and fopitasvir), and analyzed the prevalence of baseline RASs and treatment-emergent RASs. A total of 94 treatment-na?ve HCV genotype (GT)-1b (n = 63) and GT-2a (n = 31) Chinese patients were enrolled in three phase 1b clinical trials. We investigated RASs in 77 patients with next generation or Sanger sequencing. In the 7-day trial of yimitasvir phosphate, the mean maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts (0.83 vs. 2.45 log10 IU/mL and 1.92 vs. 2.63 log10 IU/mL). In the 3-day trial of KW-136, the mean maximum HCV RNA decrease in patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30, 60 and 120 mg cohorts (1.58 vs. 2.89 log10 IU/mL, 3.16 vs. 4.09 log10 IU/mL and 3.00 vs. 5.04 log10 IU/mL, respectively). In the 3-day trial of fopitasvir, only 30 mg group had baseline Y93H or Y93Y/H, and the average maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation (1.45 vs. 3.59 log10 IU/mL). In the three trials, baseline RASs were observed in 54 patients (70.1%; 54/77). The most prevalent baseline RASs were Y93H and Y93Y/H (18.2%; 14/77), followed by L31M (16.9%; 13/77). The most common RASs after single administration of DAA were Y93H and Y93Y/H. Our data could provide reference for future clinical treatment and clinical trial.

    Preclinical efficacy of a novel cyclin-dependent kinase 9 inhibitor, QHRD107 against acute myeloid leukemia
    Yan Zhou, Hengwen Song, Zhichao Shao, Bomin Yin, Ximei Fu, Dianyou Xie, Lijun Wei
    2021, 30(2):  146-156.  DOI: 10.5246/jcps.2021.02.012
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    QHRD107 is a specific inhibitor of cyclin-dependent kinase 9 (CDK9). It is a highly potent antiproliferative agent against leukemia cells in vitro. Oral administration of QHRD107 to mice bearing acute myeloid leukemia tumors markedly inhibited tumor growth. In Molm-13 orthotopic model, QHRD107 resulted in remarkable prolongation of animal life span. After single oral administration of QHRD107 to Molm-13 xenograft model, QHRD107 was quickly absorbed and distributed to tumor with high concentration within 1 h. Tumor half-life time (T1/2) was three times longer compared with that of plasma. Under the high exposure of QHRD107 in tumor tissue, fast down-regulation of anti-apoptotic protein Mcl-1 mRNA was noted. Reduction of Ki-67 staining in tumor tissue further demonstrated the apoptosis of tumor cells. Therefore, the results provided evidence that QHRD107 at therapeutic dose had significant antitumor activity against AML cell lines.

    Identification of major compounds of total flavonoids from Smilax china and evaluation of anti-inflammatory effect on phenol mucilage-induced pelvic inflammation in rats
    Jiaqian Chen, Chen Jin, Bolun Xu, Huang Zhan, Rongrong Fu, Fengqin Li, Huilian Huang
    2021, 30(2):  157-168.  DOI: 10.5246/jcps.2021.02.013
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    As a Chinese medicinal plant, Smilax china is traditionally used in the treatment of pelvic inflammatory disease (PID). Flavonoids have been identified as the anti-inflammatory bioactive fraction. However, the high content of total flavonoids has not been extracted from S. china. The therapeutic effects and mechanisms of total flavonoids are still unknown. In the present study, we aimed to obtain the effective parts of flavonoids in S. china, and elucidate the mechanism of action on PID. The anti-inflammatory effect was evaluated on phenol mucilage-induced pelvic inflammation in rats. This was the first time that total flavonoids in high concentration (up to 55.6%) were obtained in S. china. A total of 15 compounds were separated and identified by NMR, and the total flavonoids were detected with HPLC. TFSC caused a reduction in serum levels of IL-6 and IL-1β. These results suggested that TFSC had a significant anti-PID effect, probably due to inhibition of the inflammatory reaction.

    A comparative study on different multiple cropping patterns of Bupleurum chinense
    Jiquan Liu, Yu Wang, Jianing Liu, Xin Liu, Runli He
    2021, 30(2):  169-178.  DOI: 10.5246/jcps.2021.02.014
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    Bupleurum chinense is a genuine medicinal material in Shanxi Province, and planting B. chinense is one of the main sources for local farmers to increase their income. In B. chinense cultivation, wheat-B. chinense, maize-B. chinense and soybean-B. chinense are commonly used as multiple cropping patterns. In the present study, we studied the effects of three different multiple cropping patterns on N, P and K levels of soil, photosynthetic parameters, agronomic characteristics, saikosaponin A, C and D contents, yield and economic benefits of B. chinense. The results showed that the soybean-B. chinense multiple cropping pattern was beneficial to the enrichment of N in the soil, thus promoting photosynthetic parameters, growth, saikosaponin accumulation, yield and economic benefits of B. chinense. It is suggested that soybean-B. chinense multiple cropping was an appropriate multiple cropping pattern for local cultivation of B. chinense.

    News
    The research group of Professor Wanliang Lv has made progress in the study of targeted functional liposomes against drug-resistant breast cancer
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(2):  179-180. 
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    The research group of Professor Wanliang Lv has made progress in the study of targeted functional liposomes against drug-resistant breast cancer.
    The group of Professor Tao Liu used biosynthesis strategies to achieve diverse modifications of protein drugs
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(2):  181-182. 
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    The group of Professor Tao Liu used biosynthesis strategies to achieve diverse modifications of protein drugs.
    The group of Professor Tao Liu used a supramolecular recognition strategy to achieve reversible regulation of protein
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(2):  183-184. 
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    The group of Professor Tao Liu used a supramolecular recognition strategy to achieve reversible regulation of protein.
    The group of Professor Pengfei Tu/Kewu Zeng has made progress in the study of anti-cerebral ischemia target of Cistanche deserticola
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(2):  185-186. 
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    The group of Professor Pengfei Tu/Kewu Zeng has made progress in the study of anti-cerebral ischemia target of Cistanche deserticola.
    The research group of Professor Suwei Dong has made progress in the chemical synthesis and glycosyl function study of glycoproteins
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(2):  187-188. 
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    The research group of Professor Suwei Dong has made progress in the chemical synthesis and glycosyl function study of glycoproteins.