Table of Content

Volume 26 Issue 7
26 July 2021

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General considerations on bioanalytical methods for comparative evaluation of biosimilars immunogenicity

CHE Jinjing, LI Na

2021, 26(7):  721-728.  doi:10.12092/j.issn.1009-2501.2021.07.001

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Based on the principle of progressive comprehensive comparability, must be similar to reference drugs in terms of physicochemical properties, bioactivity, pharmacokinetics, efficacy, and safety (including immunogenicity). The objective of the immunogenicity assessment of biosimilars is to assess potential differences in the incidence and severity of human immune responses between biosimilars and reference drugs. No clinically significant differences in immune responses between the two products is a key factor in demonstrating biosimilarity. The influencing factors include subjects, sampling scheme, product factors and bioanalysis methods. An important issue in bioanalysis is the selection of two-assay (based on biosimilars and reference agents respectively) or one-assay (based on biosimilars respectively) as the best method for comparative immunogenicity assessment. In order to support the development of biosimilars, this paper focuses on the use of One-assay to evaluate immunogenicity based on biosimilars. The development and validation of an ADA assay for biosimilar drugs should include all validation of the original drug. In addition, biosimilars need to be compared with reference to confirmation thresholds, antigenic equivalence, and drug tolerance to assess the ability of biosimilars and reference drugs to bind in a similar manner to positive controls. ADA data analysis should be combined with PK/PD parameters and clinical events.

Reversal of 5-fluorouracil resistance in hepatocellular carcinoma cells by inhibiting ribonucleotide reductase M2 

YU Saihong, ZHENG Xiaoliang, PU Yiyi, YAN Dongmei, WANG Xiaoju, YU Jie

2021, 26(7):  729-737.  doi:10.12092/j.issn.1009-2501.2021.07.002

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AIM: To investigate the role of ribonucleotide reductase M2 (RRM2) in 5-fluorouracil (5-FU) resistance of HCC cells and to develop potential strategies to enhance the sensitivity of HCC cells to 5-FU.  METHODS: The expression of RRM2 was examined by Western blot in BEL/5-FU cells and BEL7402 cells. The expression of RRM2 was down-regulated through RNA interference (RNAi) technology and the activity of RRM2 was inhibited by the RRM2 inhibitor 3-AP. The cell proliferation ability was detected by CCK-8 assay and colony formation assay, and the apoptosis was analyzed by Confocal high-content system. RESULTS: The expression level of RRM2 was increased by 2.5-fold in BEL/5-FU cells compared with BEL7402 cells. Compared with control siRNA, the half maximum inhibitory concentration IC50 of 5-FU in BEL/5-FU cells was decreased by about 50% via RRM2 down-regulation and the cell colony ability was significantly weakened in the treatment of 5-FU. The 5-FU IC50 of BEL/5-FU cells treated with 3-AP was decreased by about 40%, and the cell colony ability was significantly weakened and cell apoptosis was enhanced. CONCLUSION: RRM2 is related to the drug resistance of HCC cells to 5-FU. This study reverses the drug resistance of HCC cells to 5-FU by inhibiting the activity of RRM2, providing a new target and a new idea for improving the efficacy of 5-FU chemotherapy for HCC.

Effect of SLC7A11 in dexmedetomidine pretreatment induced reduction of ferroptosis caused by intestinal ischemia-reperfusion injury in mice 

ZHANG Tianxue, ZHANG Lei, HAO Yingxiang, GAO Mingjing, WU Lin, LENG Yufang

2021, 26(7):  738-743.  doi:10.12092/j.issn.1009-2501.2021.07.003

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AIM: To evaluate the effect of SLC7A11 in dexmedetomidine pretreatment induced reduction of ferroptosis caused by intestinal ischemia-reperfusion (II/R) injury in mice.  METHODS: Twenty-four healthy meal SPF C57BL/6J mice, aged 8 weeks, weighing 22-25 g, were randomly divided into Sham operation group (S group), intestinal I/R group (II/R group), dexmedetomidine group (DEX group) and dexmedetomidine plus SLC7A11 inhibitior group (DIKE group), with 6 mice in each group. Intestinal ischemia was induced by occluding the superior mesenteric artery for 45 min followed by 30 min of reperfusion to establish the model of II/R injury. In DEX and DIKE groups, Dexmedetomidine 25 μg/kg was intraperitoneally injected at 30 min before clamping the superior mesenteric artery. The same amount of normal saline was injected in the S group and the II/R group. In DIKE group, SLC7A11 inhibitior Imidazole ketone erastin 50 mg/kg was intraperitoneally injected at 90 min before ischemia. Mice were sacrificed 30 min after reperfusion, and small intestinal tissues in length 5 cm away from the ileocecal valvum were obtained for microscopic examination of pathological changes of intestinal mucosa and for determination of contents of Fe2+ and malondialdehyde (MDA) and superoxide dismutase (SOD) activity (by colometry), reduced glutathione (GSH) content (by microplate method), and expression of SLC7A11, glutathione peroxidase 4 (by Western blot). Intestinal damage was assessed and scored according to Chiu. RESULTS: Compared with group S, Chiu's score, Fe2+ and MDA contents were significantly increased, the SOD activity and GSH content were decreased, and the expression of SLC7A11 and GPX4 was down-regulated in the other 3 groups (P<0.05). Intraperitoneal injection of dexmedetomidine significantly decreased Chiu's score, Fe2+ and MDA contents, increased SOD activity and GSH content, and upregulated SLC7A11 and GPX4 expression (P<0.05). Intraperitoneal injection of the SLC7A11 inhibitor produced the opposite result. CONCLUSION: Dexmedetomidine can protect intestine tissue from ischemia-reperfusion injury, which maybe correlates with activating SLC7A11 and inhibiting ferroptosis.

Effects of metformin on epithelial-mesenchymal transition of rat alveolar epithelial type II cells induced by TGF-β1

HAO Wei, ZUO Dongze, ZHANG Junxiu, JIANG Lili, XIONG Ying, YANG Jieren

2021, 26(7):  744-752.  doi:10.12092/j.issn.1009-2501.2021.07.004

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AIM: To observe the effect of metformin (Met) on the endothelial-mesenchymal transition (EMT) of rat alveolar epithelial type II cells and its mechanism. METHODS: The RLE-6TN cells were divided into 6 groups as follows: Control group; transforming growth factor-β1 (TGF-β1) group in which cells were incubated with TGF-β1 (5 ng/mL) for 48 h; TGF-β1+Met (1, 10, 100 μmol/L) group in which cells were pre-treated with Met (1, 10, 100 μmol/L) for 1 h, and then subjected to TGF-β1 (5 ng/mL) for 48 h; Met (100 μmol/L) group in which cells were incubated with Met (100 μmol/L) for 48 h. CCK-8 method was used to detect the cell proliferation. RT-PCR detected α-smooth muscle actin (α-SMA), vimentin, E-Cadherin, tight junction protein-1 (ZO-1), collagen I and collagen III mRNA expression. Western blotting was used to detect the protein expression of α-SMA, vimentin, E-Cadherin, ZO-1, collagen I, collagen III and levels of phosphorylated Smad2/3 and extracellular regulated protein kinases (ERK1/2). RESULTS: Metformin significantly inhibited the proliferation of RLE-6TN cells induced by TGF-β1 (P<0.05 or P<0.01), reduced the mRNA and protein expression of α-SMA, vimentin, collagen I, collagen III, and decreased the protein phosphorylation of Smad2/3 and ERK1/2 Level (P<0.05 or P<0.01) when compared with the TGF-β1 group. Conversely, metformin treatment increased the mRNA and protein expression of E-cadherin and ZO-1 (P<0.05 or P<0.01) compared with the TGF-β1 group. CONCLUSION: Metformin (10, 100 μmol/L) exhibits certain inhibitory effect on the EMT of RLE-6TN cells induced by TGF-β1, and its beneficial effects may be associated with the inhibition of the phosphorylation of Smad2/3 and ERK1/2.

Nobiletin inhibits neonatal rat cardiomyocytes hypertrophy induced by high glucose

LIU Xiaoping, LAI Xiangmao, OUYANG Zizhang, JIANG Sheng, ZHANG Ying

2021, 26(7):  753-759.  doi:10.12092/j.issn.1009-2501.2021.07.005

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AIM: To investigate the effect of nobiletin (Nob) on cardiomyocyte hypertrophy induced by high glucose and its mechanism.  METHODS: Neonatal rat cardiomyocytes (NRCMS) were stimulated with high glucose (HG) to establish cardiomyocyte hypertrophy and nobiletin was given. Cell viability was measured by MTT assay. C-myc and Nppa mRNA levels were detected by qRT-PCR. Cellular surface area was detected by immunofluorescence, and Nrf2 and HO-1 protein expressions were detected by Western blot. RESULTS: After stimulation with 33.3 mmol/L HG for 48 h, the survival rate of NRCMS was significantly decreased, C-myc, Nppa mRNA levels and cellular surface area were significantly increased, Nrf2 and HO-1 protein expression were significantly decreased (P<0.05). After Nob treatment, compared with HG group, cellular surface area, Nrf2 and HO-1 protein expression were significantly increased, C-myc and Nppa mRNA levels were significantly decreased. The above indexes were reversed by using Nrf2 inhibitor. CONCLUSION: Nob inhibits cardiomyocyte hypertrophy induced by high glucose, and its mechanism may be related to the activation of Nrf2/HO-1 signaling pathway.

Dose selection of obeticholic acid in hepatic impairment patients and the review consideration of FDA

GAO Lili, CHEN Rui, LI Lujin, ZHENG Qingshan

2021, 26(7):  760-767.  doi:10.12092/j.issn.1009-2501.2021.07.006

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The clinical trial of OBCA (OCALIVA) in the treatment of primary biliary cirrhosis (PBC) shows its efficacy. As it is difficult to conduct sufficient clinical studies in moderate and severe hepatic impairment population, the applicant and the FDA theorem have different opinions based on the same model, such as population PK, exposure-response and physiologically-based PK (PBPK). The applicant considers that the increase in the exposure of drug in liver tissue is limited, and there is no need for dose adjustment, that is, 5 mg, once a day. FDA believes that the influencing factors of the PBPK model have not been fully taken into account and the validation of the PBPK is not robust with a wide variability, and there is also a risk of high blood drug exposure in patients. It is recommended to significantly reduce the dose, that is, 5 mg, once a week, no more than 10 mg, per week at least 3 days interval, and accordingly written into the medication instructions. After approval many patients with hepatic impairment did not take medicine according to the instructions,therefore overdosed, resulting in death. The results fully prove that the original considerations and decisions of FDA have been verified, and the experience and lessons of this example once again suggest that modeling and simulation need bold assumptions and careful verification.

Relationship between human cholesteryl ester transfer protein rs5882 gene polymorphism and postoperative cognitive dysfunction

ZHOU Minmin, YU Lu, HAN Chao, GU Damin, LEI Daoyun

2021, 26(7):  768-774.  doi:10.12092/j.issn.1009-2501.2021.07.007

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AIM: To investigate the relationship between human cholesteryl ester transfer protein CETP gene polymorphism and postoperative neurocognitive disorders (PND).  METHODS: A total of 124 elderly patients over 65 years of age who underwent elective non-cardiac surgery were enrolled in the study while 25 healthy volunteers matching age and sex were recruited as the control group. Neuropsychological tests were performed 1 day before surgery, 7 days, and 3 months after surgery. PND was determined using the Z value method. The venous blood sample of the surgical patient was taken before the operation, followed by direct gene sequencing. Statistical methods were used to calculate the correlation between CETP gene polymorphism (rs5882) and PND. RESULTS: The incidence of PND was 29.3% and 18.2% at 7 days and 3 months after operation respectively. The A allele frequency of PND patients was significantly higher than that of non-PND patients 7 days and 3 months after surgery (65.52% vs. 41.43%, 34.48% vs. 58.57%, P=0.001), while the G allele frequency in PND group lower than that of non-PND (58.33% vs. 37.86%，41.67% vs. 62.14%, P=0.004).AA genotype in PND patients was 34.48%, 38.89% at 7 days and 3 months after surgery respectively, significantly higher than 14.29%, 16.05% of non-PND (P=0.023, P=0.029). CONCLUSION: CETP rs5882 polymorphism is associated with PND and AA genotype may be a predisposing factor for postoperative PND in Chinese Han elderly patient.

Application of AUC/MIC as the therapeutic drug monitoring target of vancomycin in patients with severe infections of multi drug resistant gram positive bacteria

FU Xiangjun, HUANG Li, GUO Li, LIN Liangmo

2021, 26(7):  775-781.  doi:10.12092/j.issn.1009-2501.2021.07.008

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AIM: To discuss the application and clinical significance of the ratio of area under the curve over 24 hours to minimum inhibitory concentration (AUC24h/MIC) as the monitoring target of vancomycin in patients with severe infections of multi drug resistant gram positive bacteria (MDR G+bacteria) in our hospital.  METHODS: All patients with MDR G+bacterial infections were performed serum trough concentration of vancomycin (Ct). We used the pharmacokinetic software JPKD and Bayesian calculation to estimate the AUC24h/MIC of vancomycin (if MIC=1 mg/L). Then we compared the attainment rates of AUC24h/MIC with different Ct range, and tried to find out the probable interfering factors that might affect AUC24h/MIC and the clinical significance to take AUC24h/MIC as a predictor of curative effect and nephrotoxicity. RESULTS: Multiple linear regression analysis showed Ct had a good correlation with AUC24h/MIC. When Ct was 10-15 μg/mL, only 38.89% of the patients performed AUC24h/MIC 400-600, but when Ct was 15-20 μg/mL, up to 88.89% of the patients could achieve the recommended range. The curative effect of vancomycin seemed to have a significant correlation with patients accepting intensive care or not, rather than AUC24h/MIC. Whether use Ct＞20 μg/mL or AUC24h/MIC＞600 as an indicator to evaluate the occurrence risk of acute kidney injury(AKI) showed no differences. CONCLUSION: Patients with MDR G+bacterial infections should maintain Ct between 15-20 μg/mL, in this case, there was 88.89% probability to achieve AUC24h/MIC of 400-600. Also, the standardized testing of MIC should be proposed to improve the clinical application of vancomycin.

Clinical efficacy and safety of ixazomib in the treatment of multiple myeloma

BAO Jing, CHEN Xiaowen, XIA Liang, ZHAO Yuchen, XIA Ruixiang, XIA Hailong

2021, 26(7):  782-786.  doi:10.12092/j.issn.1009-2501.2021.07.009

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AIM: To evaluate the clinical efficacy and safety of oral proteasome inhibitor ixazomib in the treatment of multiple myeloma. METHODS: Eighty patients with multiple myeloma treated with ixazomib-containing therapy in the department of hematology, the First Affiliated Hospital of Anhui Medical University from January 2019 to December 2020 were retrospectively analyzed, including 38 patients with relapsed/refractory multiple myeloma (RRMM)and 42 patients who switched treatment due to adverse events (AEs) after initial induction therapy with bortezomib. Treatment was a two-drug or three-drug regimen containing ixazomib, and the clinical efficacy and safety of ixazomib were evaluated. RESULTS: The overall response rate (ORR) of relapsed/refractory patients was 50%, ≥ VGPR 21.05%; the ORR of patients who switched treatment was 83.33%, compared with the ORR before switching (78.57%), the response rate was further improved, of which 45.24%(19/42) patients had deepened response; the main hematological AEs included granulocyte and platelet count reduction and anemia, non-hematological AEs were mainly diarrhea and fatigue. CONCLUSION: Ixazomib shows good clinical efficacy and safety in patients with RRMM and bortezomib-intolerant MM.

1,25 dihydroxy vitamin D3 for immunoregulation in the treatment of spinal tuberculosis 

ZHANG Quan, SHI Shiyuan, HAN Guihe

2021, 26(7):  787-793.  doi:10.12092/j.issn.1009-2501.2021.07.010

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AIM: To observe the immunomodulatory effect of 1,25(OH)2D3 in the treatment of patients with spinal tuberculosis. METHODS: Patients diagnosed as spinal tuberculosis and treated according to the anti-tuberculosis regimen of 3HRZE/15HRE in the department of orthopedics, Zhejiang Integrated Chinese and Western Medicine Hospital from January 2016 to December 2019 were randomly divided into treatment group and control group. The control group was treated with routine therapy, while the treatment group was given 1,25(OH)2D3 capsule additionally. Changes of 1,25(OH)2D3, IFN-γ, IL-10 in the serum and the proportion of T-lymphocyte subsets in the blood of the two groups were observed at 4 and 8 weeks after treatment; the correlation between 1,25(OH)2D3 and other indexes of the treatment group was analyzed. RESULTS: At 4th and 8th weeks after treatment, the serum 1,25(OH)2D3 levels in the treatment group were (31.08±10.30), (26.12±6.66) pg/mL, higher than those in the control group (26.50±8.70), (21.29±6.82) pg/mL. The serum IFN-γ levels in the treatment group were (19.85±5.12), (22.14±6.83) pg/mL, higher than those in the control group (16.08±5.16), (17.03±5.34) pg/mL. At 8th weeks after treatment, the serum IL-10 levels in the treatment group was (19.18±5.46) pg/mL, lower than that in the control group (21.92±6.03) pg/mL. The levels of CD4+ and CD4+/CD8+ in the treatment group were (43.48±9.39)% and (1.88±0.57), higher than those in the control group (39.05±8.71)% and (1.58±0.46). In the treatment group, 1,25(OH)2D3 levels were positively correlated with CD4+, CD4+/CD8+, IFN-γ, and negatively correlated with CD8+, IL-10. CONCLUSION: It is necessary to supplement 1,25(OH)2D3 in the treatment of spinal tuberculosis. It can increase the level of 1,25(OH)2D3 in the blood, improve the immune function and enhance the ability of anti tuberculosis.

Interstitial ions regulate sleep and wakefulness

JIANG Jianbo, SUN Qian, DING Fengfei

2021, 26(7):  794-801.  doi:10.12092/j.issn.1009-2501.2021.07.011

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Electroencephalogram (EEG) is the super-imposed electrical signals at the scalp electrodes generated from neuronal activity. The combined signals of EEG and electromyogram (EMG) can be used to identify sleep and wake states. Therefore, factors affecting the neuronal activity could possibly modulate the state of sleep and wake. It has been well-defined in the past decades that postsynaptic neuronal activity is mediated by neurotransmitters release from presynaptic neurons. Neural circuits have been proposed to be the structural basis and functional system that regulate sleep-wake. Beside presynaptic inputs, neuronal activity can also be mediated by extracellular environment. All cellular elements of the central nervous system (CNS) are consistently exposed to the interstitial milieu. The interstitial ion compositions can affect action potential firings, neurotransmitter release, and synaptic transmission. The super-imposed single neuronal electrical activity will eventually integrate the whole brain state shift. Frontier studies suggest that the interstitial ion compositions could mirror or drive state transitions, such as, sleep, wakefulness and locomotion. Here we provide an literature review of the roles of interstitial ions in regulating neuronal activity, as well as sleep and wake state maintenances and transitions.

Ethical issues and countermeasures of early phase trials

OUYANG Chenxi, HUANG Jie, XIANG Yuxia, WANG Xiaomin

2021, 26(7):  802-807.  doi:10.12092/j.issn.1009-2501.2021.07.012

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Early phase trials refer to the early exploratory stage of transferring drug development into clinical trials. With China's strong encouragement for innovative drug research and development and enterprises vigorous investment, a large number of innovative drugs have entered early clinical trials. Early phase trials are generally based on innovative diagnosis and treatment mechanisms, pharmaceutical technology and drug delivery methods. Their research design are complex and diverse, and the new technology such as computer simulation are also widely used in the early phase trial process. These aspects are major challenges for the scientific and ethical review of early phase trials. Based on the characteristics of early phase trials, this article analyzes the ethical issues in early clinical trials such as risk uncertainty, therapeutic misunderstanding, subject compensation, breakthrough treatment, etc., and puts forward ethical countermeasures and suggestions.

Current research of drug interventions in the occurrence and development of myopia

WANG Tiantian, ZHANG Rongrong, WU Changfan

2021, 26(7):  808-813.  doi:10.12092/j.issn.1009-2501.2021.07.013

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Myopia is the most common eye disease occurring in children and adolescents. As the prevalence rates of myopia and high myopia have increased yearly, the number of individuals with low vision and blindness caused by high myopia and its complications has gradually increased. However, the mechanisms underlying the occurrence and development of myopia are currently unclear. The existing intervention methods include optical and drug measures. This article summarizes the measures implemented for the prevention and control of myopia in recent years and discusses the research progress of drug interventions for myopia, considering the aspects of clinical and animal trials.

Advances in the study of neuropeptide Y and neural mechanisms of post-traumatic stress disorder

ZHAO Jing, GUO Jianyou

2021, 26(7):  814-823.  doi:10.12092/j.issn.1009-2501.2021.07.014

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Post-traumatic stress disorder is a persistent psychological disorder that occurs for a period of time after an individual has been directly or indirectly exposed to a traumatic event, and this disorder can seriously affect the individual's daily living status and work situation. According to studies, about 1/3 of people with PTSD have the disorder for life, and the suicide rate is 6 times higher than that of the general population. The pathogenesis of the disease is still inconclusive, and the effect of conventional clinical drug therapy is limited and has significant side effects. At the same time, increasing attention has been paid to the importance of neuropeptide Y (NPY) for individuals to cope with stress and recover from traumatic events. In this paper, we explore the relationship between neuropeptide Y and the hypothalamic-pituitary-adrenal axis, Glutamate and γ-aminobutyric acid neurons, locus coeruleus-norepinephrine system, and corticotropin releasing factor, which are closely related to posttraumatic stress disorder, to identify the neural circuit of neuropeptide Y. It may provide a new perspective for the prevention and treatment of PTSD and for the understanding of its developmental mechanisms.

Clinical pharmacological properties of alfentanil and its progress in anesthetic application 

WANG Jinhuo, GUO Jianrong

2021, 26(7):  824-829.  doi:10.12092/j.issn.1009-2501.2021.07.015

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Alfentanil is a synthetic fentanyl derivative acting on μ opioid receptors. It is a short-acting strong analgesic.  Compared with similar anesthetic drugs such as fentanyl and sufentanil, alfentanil had the lowest titer, the fastest effect, and shorter action time. The effect reached the peak 1.4 min after intravenous injection, and the maintenance time was 10-15 min. The distribution volume was small, which was in line with the three-compartment model, and was excreted through urine after liver metabolism inactivation.  Alfentanil, one of the earliest drugs in the fentanyl family, has been widely used in analgesia, sedation, anti-anxiety, induction and maintenance of anesthesia. In recent years, the use of alfentanil has tended to be short procedure, daytime surgery, reserved breathing, and outpatient anesthesia. With the recent successful development of domestic alfentanil and its gradual application in anesthesia, alfentanil is expected to become a new choice for clinical analgesia, but its clinical application experience and related studies are very limited at present. In this paper, the pharmacological characteristics of alfentanil and its application at home and abroad were reviewed in order to provide reference for the rational clinical application of alfentanil.

Efficacy and safety of antifibrinolytic therapy in the perioperative cardiovascular surgery

LI Qian, LV Hong, LIU Yue, SHI Jia

2021, 26(7):  830-835.  doi:10.12092/j.issn.1009-2501.2021.07.016

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Massive hemorrhage and allogeneic blood transfusion are common complications in the perioperative period of cardiovascular surgery, which can significantly increase the incidence of adverse events and worsen the long-term prognosis. Therefore, perioperative blood protection strategies have been widely promoted and applied in clinical practice. Additionally, as the core strategy, antifibrinolytic therapy can tremendously reduce perioperative bleeding and blood transfusion during cardiovascular surgery. Tremendous clinical trials have confirmed the efficacy and safety of lysine analog in adult cardiopulmonary bypass cardiac surgery. However, evidence-based medicine on the effectiveness and safety of antifibrinolytic drugs in off-pump cardiovascular surgery and pediatric cardiovascular surgery is still insufficient; there still needs further research and concern. In addition, the topical use of antifibrinolytic drugs and related molecular mechanisms have been reported in recent years. Therefore, this article reviews the efficacy and safety of perioperative antifibrinolytic therapy in cardiovascular surgery.

Research progress of small molecule inhibitors that reverse tumor drug resistance by regulating tumor glucose metabolism

YANG Hechun, SHI Daohua

2021, 26(7):  836-840.  doi:10.12092/j.issn.1009-2501.2021.07.017

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Tumor drug resistance is currently one of the most difficult clinical problems. There are many theories on the mechanism of tumor drug resistance, and metabolic reprogramming is one of its mechanisms. Tumor cells undergo metabolic reprogramming to meet the energy requirements of proliferation, especially the changes in the glucose metabolism. This article reviews the glucose metabolism reprogramming-related enzymes and the associated small molecule inhibitors that reverse tumor drug resistance.