Table of Content

Volume 26 Issue 10
26 October 2021

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Applications of Drug Interaction Study in New Drug Development and Regulartory Decision-making

SUN Bo, FU Shujun, CHEN Guiliang, LI Li

2021, 26(10):  1095-1102.  doi:10.12092/j.issn.1009-2501.2021.10.001

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Drug-drug interactions (DDI) change dose-response relationships, and may result in low efficacy or high toxicity, which are important considerations especially in medical practice with multiple-drug therapies. Predicting clinically significant drug interactions during new drug development is an important part of benefit and risk assessment in drug development and review. This article summarizes the purpose and significance of drug interactions in new drug development, the main content and precautions of DDI studies in vivo and in vitro. Drug interaction studies on novel drug approvals for 2020 in the National Medical Products Administration (NMPA) and US Food and Drug Administration (USFDA) are examined, respectively. It aims to provide reference for DDI studies and regulatory reviews in new drug development in our country.

Inhibitory and scavenging ability of ambroxol combined with levofloxacin on the bacterial biofilm of Klebsiella pneumoniae

LI Xiaoning, YU Xiao, HUANG Chenlei, CAO Ruonan, LI Jie, ZHU Guoping

2021, 26(10):  1103-1110.  doi:10.12092/j.issn.1009-2501.2021.10.002

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AIM: To study the inhibitory and scavenging effects of ambroxol combined with levofloxacin on the bacterial biofilm of Klebsiella pneumoniae, and to provide a new strategy to treat and antagonize the formation of the biofilm. METHODS: We collected Klebsiella pneumoniae of different resistance and divided them into sensitive group (wild bacteria group), ESBLs group and CRKP group with 15 strains in each group and performed biological semi-quantitative detection of its biofilm by crystalline violet staining method. After selecting 3 strains with similar membrane yields from each group, we determined the minimum inhibitory concentration (MIC) of ambroxol and levofloxacin against Klebsiella pneumoniae by micro broth dilution method.In addition, we determined the effects of ambroxol in different concentrations on the MIC of levfloxacin by the micrdilution checkerboard techniques and calculated the partial inhibitory concentration index (FIC) to determine the joint effect and select the best synergistic concentration. Finally, the effects of ambroxol and levofloxacin in different concentrations on the inhibition formation test and removal test of Klebsiella pneumoniae biofilm were observed by crystal violet method combined with confocal laser scanning microscopy. RESULTS: We found that all three groups of bacterial biofilms became mature on the 5th day, and the sensitive group was easier to form and produce biofilm more than the ESBLs and CRKP groups (F=3.725, P=0.032). It was showed that the geometric average of levofloxacin MIC value in the three groups decreased significantly. And the selected strains all showed a synergistic effect on the two-drug combination.In the biofilm test, as the concentration of ambroxol increased, its inhibition rate reached more than 75%, but its biofilm removal rate did not reach 70%. CONCLUSION: Our study support that ambroxol combined with levofloxacin can inhibit the bacterial biofilm of Klebsiella pneumoniae early, and its optimal synergistic concentration is 0.49 mg/mL (ambroxol) + 4 μg/mL (levofloxacin).

Study on drug-resistant phonotype and plasmid-mediated quinolone resistance genes in Acinetobacter baumannii isolates

YUAN Xing, SU Yan, XU Zhenguo, LI Zisheng

2021, 26(10):  1111-1117.  doi:10.12092/j.issn.1009-2501.2021.10.003

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AIM: To investigate drug resistance of Acinetobacter baumanii strains isolated in the hospital from 2018 to 2019, and explore plasmid-mediated delivery of quinolones resistance genes (PMQR) in Acinetobacter baumannii, to provide references for the clinical therapy of infections and to analysis the genetic mechanisms of resistance by aid of molecular methods．METHODS: Bacteria were identified by VITEK-2 compact System, the results of antibiotics susceptibility test was determined by using microdilution method MIC．We amplified Genes of qnrA,B,C,D, S,aac(6’)-Ib and qepA on plasmid by PCR, and PCR products of each resistant gene for sequencing analysis wrer random selected. We analyzed the results of antibiotics susceptibility of 152 clinical isolates based on WHONET5.6 software．RESULTS: In the past two years, 152 strains of Acinetobacter baumanii have been detected from clinical specimens. The antibiotics resistance rate of Acinetobacter baumanii isolates was an increasing trend year by year．PCR indicated that some strains of Acinetobacter baumanii have products of aac(6’)-Ib and qnrB gene, 29.6%（45/152） strains carrying aac(6’)-Ib and 1.3% (2/152) strains carrying qnrB, there were no products of qnrA,C,D,S and qepA genes on plasmid．CONCLUSION: The current drug-resistance rate among Acinetobater baumannii strains in Hefei to common antibiotics is high, and PMQR carrying rate is lvw．

Correlation of BRCA1 gene polymorphism with chemosensitivity and prognosis of metastatic esophageal squamous cell carcinoma treated with cisplatin combined with capecitabine

TIAN Yali, FENG Lin, ZHAO Wan, GU Min, SHEN Hanjing, CHAI Xiaoyan

2021, 26(10):  1118-1126.  doi:10.12092/j.issn.1009-2501.2021.10.004

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AIM: To explore the effect of single nucleotide polymorphism (SNP) of breast cancer susceptibility gene 1 (BRCA1) on chemotherapy sensitivity and survival prognosis of patients with metastatic esophageal squamous cell carcinoma. METHODS: A total of 153 patients with newly treated metastatic esophageal squamous cell carcinoma who were admitted to Suzhou Science and Technology City Hospital from June 2016 to February 2020 were included and administered with cisplatin combined with capecitabine chemotherapy. Before the first chemotherapy, 5 mL of venous blood was collected to extract DNA, and the TaqMan probe method was used to detect the genotypes of the BRCA1 gene rs8176318G/T, rs799917T/C and rs1799966T/C polymorphic loci. The objective response rate (ORR) and overall survival (OS) of different genotypes were analyzed. RESULTS: Rs799917T/C polymorphism was closely related to the chemosensitivity of metastatic esophageal squamous cell carcinoma. The chemotherapy response rates of TT, TC and CC genotypes increased gradually (TT 22.5%, TC 38.6%, CC 55.3%, χ2 = 8.041, P=0.018). The chemotherapy response rate of the CC genotype was 4.154 times that of the TT genotype (95%CI: 1.54911.141, χ2=8.007, P=0.005); the chemotherapy response rate of the TC+CC genotype was 2.678 times that of the TT genotype (95%CI: 1.1606.179, χ2=5.329, P=0.021). KaplanMeier analysis showed that the rs1799966T/C polymorphism was related to the survival time of patients, and the median OS of carriers of TT, TC and CC genotypes showed a gradually prolonging trend (TT 8.5 months, TC 12.1 months, CC 13.8 months, χ2 =11.864, P=0.003); The median OS of patients with TC+CC genotype was 12.6 months, which was significantly longer than that in the TT group (χ2=10.515, P=0.001). COX regression model analysis showed that the polymorphism of rs1799966T/C was still an independent prognostic factor of OS. There was no statistical correlation between rs8176318G/T polymorphism, chemotherapy response and prognosis. CONCLUSION: The rs799917 polymorphism of BRCA1 gene is associated with the sensitivity of cisplatin combined with capecitabine in metastatic esophageal squamous cell carcinoma, and rs1799966 polymorphism may affect the prognosis of patients.

Analysis of the effective components and mechanism of Yufang Fangji II for prevention of COVID-19 based on UHPLC-Q-TOF/MS and network pharmacology

YU Tianyi, JIAO Guangyang, HUANG Doudou, CHEN Yong, XU Deduo, QIU Shi, CHEN Wansheng, ZHANG Feng, WANG Bolong

2021, 26(10):  1127-1145.  doi:10.12092/j.issn.1009-2501.2021.10.005

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AIM: The main chemical components of Yufang Fangji II (Hubei Fang) of COVID-19 were studied systematically and combined with network pharmacology to provide a reference for the study of its effective substances. METHODS: Ultra high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-Q-TOF/MS) was applied to identify the absorbed components of the prescription in rat plasma. TCMSP database and Swiss Target Prediction data platform were used to predict the target of the identified blood components, and network visualization software Cytoscape 3.7.2 was used draw the association network diagram, and GO enrichment analysis and KEGG pathway enrichment analysis were conducted for the key targets. With the help of CB-Dock online molecular docking platform, the molecular docking of key targets and blood entering compounds was carried out, and the docking combination with good affinity value was displayed by ligplot software to verify the preventive effect of Yufang Fangji II on COVID-19. RESULTS: A total of 52 chemical components identified in the prescription, in which 13 components were absorbed in the rat plasma as the prototype, and they were from Astragalus membranaceus, Atractylodes macrocephala, Saposhnikoviae Radix, Lonicerae Japonicae Flos, and Citri Reticulatae Pericarpium, respectively. These compounds were recognized to act on 17 core targets, including mapk3, TNF and other targets related to inflammation, MPO and other targets related to oxidative stress, VEGFR, KDR and other targets related to vascular endothelium. The results of molecular docking showed that the absorbed components had good binding activity with the key targets. CONCLUSION: Compounds in Yufang Fangji II are involved in regulating inflammation, oxidative stress, vascular and cellular physiological activities, which have preventive effects on COVID-19 through regulating IL-17, PI3K Akt, MAPK and other pathways.

Effects of different postpartum withdrawal time of tenofovir on hepatitis B virus markers, virology and biochemical indexes

TAO Chengjing, LIU Shourong, CHENG Xiaoxian, HU Jiannv, BAI Xiuli, ZHANG Suying, ZHAO Chun, ZUO Zhongbao

2021, 26(10):  1146-1152.  doi:10.12092/j.issn.1009-2501.2021.10.006

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AIM: To evaluate the effect of TDF withdrawal time on changes of serum HBV-M, HBV DNA and ALT level in the mother-to-child blocking of the maternal population. METHODS: A prospective, randomized and controlled study was conducted. The 120 pregnant women with HBV who took TDF during 24 to 28 weeks of gestation were randomly divided into group A (withdrawal at delivery) and group B (withdrawal at 4 weeks postpartum), levels of HBV-M,HBV DNA, and ALT at different times were detected. The results were statistically analyzed by Wilcoxon Rank-sum test and χ2 test. RESULTS: In total, 106 pregnant women have completed testing and follow-up, including 56 in group A and 50 in group B. The levels of HBsAg showed no significant difference in both groups and between the two groups (P>0.05). The levels of HBeAg (M=2.920Log10S/CO) and HBV DNA (M=1.477Log10copies/mL) of group B at withdrawal were significantly lower than group A (M=3.045Log10S/CO, M=2.647Log10 copies/mL). The difference were statistically significant (Z=3.126, P=0.002; Z=－2.940, P＜0.001). The HBeAg serological conversional rate of group B was 22.00%(11/50), which was higher than group A ［8.93% (5/56)］, but it was not statistically significant (P>0.05). The ALT abnormal incidence rate after withdrawal (41.07% in group A and 40.00% in group B) were significantly higher than during pregnancy (19.64% in group A, 16.00% in group B). The difference were statistically significant (group A: χ2=6.081, P=0.014; group B: χ2=7.143, P=0.008); The result of group A and group B compared each was no statistics significant (χ2=0.238, P=0.625). About women with abnormal ALT during pregnancy, the abnormal incidence rate of ALT in group A after withdrawal (100%) was significantly higher than in group B (62.50%) , and the difference was statistically significant (Z=0.696, P=0.048). CONCLUSION: The levels of HBsAg, HBeAg, HBV DNA and ALT have no difference between group A (withdrawal at delivery) and group B(withdrawal at 4 weeks after delivery). About women with abnormal ALT during pregnancy, people in group A show more incurrence than group B after drug withdrawal. Pregnant women with abnormal ALT during pregnancy should enhance postpartum monitoring and delay the drug time when necessary.

Effect of acute normovolemic hemodilution autologous blood transfusion on the EEG bispectral index and muscle relaxation in elderly patients undergoing orthopedic surgery

YIN Lei, XU Jiaming, WU Jingyi, DUAN Lishuang, WEI Hanwei, JIN Xiaoju, GUO Jianrong

2021, 26(10):  1153-1158.  doi:10.12092/j.issn.1009-2501.2021.10.007

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AIM: To observe the effect of acute normovolemic hemodilution (ANH) autologous blood transfusion on the EEG bispectral index and muscle relaxation in elderly patients undergoing orthopedic surgery to explore the influence of autologous blood transfusion containing anesthetic components on the quality and safety of postoperative anesthesia recovery. METHODS: Forty patients, aged 65-75, weighing 55-80 kg, ASA grade I-II, with an estimated intraoperative blood loss of more than 600 mL, were selected for elective orthopedic surgery. The patients were randomly divided into two groups (n=20): group A was given acute normovolemic hemodilution (ANH), and the target value of Hct was 28%-30% after induction of anesthesia; group B was the control group which was given routine fluid infusion during operation without ANH. Bispectral index (BIS), TOF values and plasma concentrations of propofol and cisatracurium were measured at the beginning of autotransfusion (T1), 10 min (T2), 20 min (T3), 30 min (T4), 40 min (T5), 50 min (T6) and 60 min (T7) of autologous blood transfusion. The changes of blood gas before operation (T0) and at T7 time point were observed and recorded. The time of extubation of tracheal tube and the quality of recovery were observed. RESULTS: The BIS value of group A was significantly lower than that of group B at T6 and T7 (P<0.05), and the TOF value of group A was significantly lower than that of group B at T5, T6 and T7 (P<0.05); there was no significant difference between the blood concentrations of propofol and cisatracurium between group A and group B (P>0.05); the lactic acid value of group A at T7 was significantly higher than that of group B (P<0.05); the time of tracheal extubation in group A was significantly longer than that in group B (P<0.05); the Aldrete score of group A was significantly lower than that of group B (P<0.05). CONCLUSION: For patients with acute normovolemic hemodilution, autologous blood transfusion after operation can deepen the depth of anesthesia, enhance muscle relaxation effect, and delay the recovery of respiratory function and extubation time in elderly patients.

Research progress of glutamine metabolism in liver cancer

LIU Zhuo, TAN Xiaoning, ZENG Puhua

2021, 26(10):  1159-1166.  doi:10.12092/j.issn.1009-2501.2021.10.008

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Liver cancer is one of the most dangerous malignant tumors in China. It has the characteristics of high mortality and occult onset. At present, the treatment of liver cancer is mainly targeted drugs, surgery and chemoradiotherapy, which is prone to high recurrence rate and strong drug resistance. In this paper, glutamine metabolism as the breakthrough point, the glutamine metabolism enzymes and related genes related to liver cancer are reviewed, in order to provide an open new idea for the pathogenesis and drug treatment of liver cancer.

Neutrophil extracellular traps and its role in gouty diseases

YI Hong, GU Bing, CHEN Yunian, LI Huanan

2021, 26(10):  1167-1173.  doi:10.12092/j.issn.1009-2501.2021.10.009

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Neutrophil extracellular traps (NETs) are an important part of the innate immunity. They are mainly involved in the occurrence of gout disease through NADPH oxidase 2-dependent pathways and it is related to the spontaneous remission of gouty arthritis and the formation of tophi. These pathological features can be analyzed by methods such as electron microscopy and immunohistochemical staining. In order to further explore the molecular mechanism of NETs and discover potential drug targets for gouty arthritis, this article summarizes its role in gouty diseases and related detection techniques.

Pharmacological research and clinical applications progress of Lianhua Qingwen capsules/granules in respiratory diseases

YIN Yujie, CHANG Liping

2021, 26(10):  1174-1180.  doi:10.12092/j.issn.1009-2501.2021.10.010

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Lianhua Qingwen capsules/granules is an innovative Chinese medicine developed under the guidance of the TCM collateral disease theory. It has the efficacy of "clearing heat and removing toxin, ventilating the lungs and discharging heat". In 2003, it was approved as a new drug by the China National Medical Products Administration, through expedited approval during/SARS, and now, it has become a representative proprietary Chinese medicine for the treatment of infectious diseases of the respiratory system. Pharmacodynamic studies have revealed that LianhuaQingwen has broad-spectrum antiviral, antibacterial and anti-inflammatory, antipyretic, cough-relieving and immunoregulation effects. Clinically it has been used in the treatment of communicable and infectious respiratory diseases such as COVID-19, influenza, upper respiratory infection, pulmonary infections, acute exacerbation of chronic obstructive pulmonary disease, etc. and has achieved remarkable curative effects.

Research progress of dynamic regulation of lysine acetylation in heart disease

ZHAO Yuan, NIE Qianwen, YIN Jiangyan, HUAN Xuan, TIAN Meixiang, ZHANG Zhengyi

2021, 26(10):  1186-1192.  doi:10.12092/j.issn.1009-2501.2021.10.012

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Reversible post-translational modification of proteins is an important process in the physiological regulation of all tissues, including the heart. Lysine acetylation occurs in all organisms, including prokaryotes, and is regulated by a balance between lysine acetyltransferase (adding acetyl to the ε-amino group of lysine) and deacetylase (acetyl group that removes lysine ε-amino group). The heart is an organ rich in acetylated lysine, but the role of acetylated lysine in the heart remains to be elucidated. Therefore, in this paper, we systematically reviewed the gene list of acetyltransferase and deacetylase in mammalian genome and indicated their mRNA expression. The purpose of this study is to discover the research progress of dynamic regulation of lysine acetylation in heart disease and to provide a theoretical basis for the discovery of molecular targets.

Research progress of mitochondrial energy metabolism involved in the pathogenesis of depression

JIN Jing, CHENG Hong

2021, 26(10):  1193-1199.  doi:10.12092/j.issn.1009-2501.2021.10.013

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Major depressive disorder (MDD) is usually an affective disorder characterized by anhedonia, cognitive decline, and social disorders. In recent years, some studies have shown that energy metabolism disorder is widespread in chronic stress models and MDD patients. Mitochondria play a central role in energy metabolism and are also involved in the regulation of oxidative stress and cell apoptosis. Thus, the abnormal changes in mitochondrial metabolism may be related to the occurrence of depression. This review summarizes the research progress of mitochondrial energy metabolism involved in the pathogenesis of depression, so as to provide reference for the research of the pathogenesis of depression and new treatment strategies based on mitochondria.

Research Progress of Pharmacogenomics of Dabigatran Etexilate and Rivaroxaban

2021, 26(10):  1200-1207.  doi:10.12092/j.issn.1009-2501.2021.10.014

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Dabigatran etexilate and rivaroxaban, as two representative new oral anticoagulants, have been widely used in clinical anticoagulation due to their fixed dosage and superior safety. However,for special populations, precise medication based on pharmacogenomics is still necessary.Most of the existing research data confirm that multiple drug gene polymorphisms are closely related to the patient's blood drug concentration and/or stroke events, but some studies have reached conflicting conclusions. Therefore, this article intends to take the genetic polymorphism as the starting point to review the research progress related to the pharmacogenomics of Dabigatran Etexilate and Rivaroxaban, in order to expand the individual differences in people’s response to Dabigatran Etexilate and Rivaroxaban.

immunogenicity of bispecific antibodies

Min CHEN

2021, 26(10):  1208-1212.  doi:10.12092/j.issn.1009-2501.2021.10.015

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The term bispecific antibody (bsAb) is used to describe antibodies that can recognize and bind two different antigens. Compared with the regular therapeutic antibodies, bsAbs have many advantages, such as higher sensitivity, better specificity, and are able to block multiple disease pathways simultaneously. So far, 3 bispecific antibodies have been marketed and nearly 100 are in clinical development all over the world, showing a broad development prospect. Immunogenicity of bispecific antibodies refers to the fact that the drugs will cause the immune response and produce anti-drug antibodies after entering the body, which may affect the pharmacokinetic and pharmacodynamic properties of the drugs. In this paper, the research progress on the immunogenicity of catumaxomab, blinatumomab and emicizumab was reviewed, with a view to providing reference for the safety, efficacy, and rational clinical application of bispecific antibodies.