Chinese Journal of Clinical Pharmacology and Therapeutics

Expert consensus on the diagnosis and treatment of insomnia in specified populations

CHEN Guihai, DENG Liying, DU Yijie, HUANG Zhili, JIANG Fan, JIN Furui, LI Yanpeng, LIU Chunfeng, PAN Jiyang, PENG Yanhui, SU Changjun, TANG Jiyou, WANG Tao, WANG Zan, WU Huijuan, XUE Rong, YANG Yuechang, YU Fengchun, YU Huan, ZHAN Shuqin, ZHANG Hongju, ZHANG Lin, ZHAO Zhengqing, ZHAO Zhongxin

2024, 29(8): 841-852. doi:10.12092/j.issn.1009-2501.2024.08.001

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Clinicians need to focus on various points in the diagnosis and treatment of insomnia. This article prescribed the treatment protocol based on the unique features, such as insomnia in the elderly, women experiencing specific physiological periods, children insomnia, insomnia in sleep-breathing disorder patients, insomnia in patients with chronic liver and kidney dysfunction. It provides some reference for clinicians while they make decision on diagnosis, differentiation and treatment methods.

Influence of hepatitis B combined with hepatic fibrosis on endogenous and exogenous metabolism and therapeutic implications

NI Jie, HONG Xiaodan, JI Ke, JIA Yuanwei, WANG Guangji, ZHANG Jingwei

2024, 29(8): 853-860. doi:10.12092/j.issn.1009-2501.2024.08.002

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AIM: To study the effect of hepatitis B combined with hepatic fibrosis on endogenous and exogenous metabolism of liver and the effect of glycyrrhizic acid combined with tenofovir (TFV) ester on anti-HBV efficacy. METHODS: Hepatitis B mouse was induced by chronic CCl4 to form a model of hepatitis B with hepatic fibrosis. H&E staining, Sirius Red Staining, α-SMA immunohistochemistry were used to detect pathological changes in liver tissue. The changes of liver endogenous metabolism in mice with hepatitis B and hepatic fibrosis were detected by metabolomics. LC-MS/MS was used to investigate the plasma and liver concentrations of TFV and its active metabolite (TFV-DP), for investigating the changes of exogenous metabolism. RESULTS: HBV+CCl4 mice showed fibrosis symptoms such as liver injury and collagen deposition. Hepatitis B combined with hepatic fibrosis affected nucleotide metabolism, amino acid metabolism, tricarboxylic acid cycle, pentose phosphate pathway and other endogenous metabolism, lowered the hepatic level of TFV-DP, and decreased the antiviral efficacy. By combining with glycyrrhizic acid or forming a self-assembled preparation, the hepatic level of TFV-DP was improved, and the antiviral efficacy was enhanced. CONCLUSIONS: Hepatitis B combined with hepatic fibrosis affected both endogenous and exogenous metabolism of liver. Different forms of combination of glycyrrhizic acid and TFV could elevate the level of TFV-DP in liver and improve the antiviral efficacy in HBV+CCl4 mice.

Study on platelet enhancement of angiogenesis in hepatocellular carcinoma and intervention effect of Cinobufagin

WU Xiaohong, CHEN Shiyu, CHEN Min, YE Mingjun, CHEN Shujun, WU Yangpei, LI Baikun, LI Qinglin

2024, 29(8): 861-869. doi:10.12092/j.issn.1009-2501.2024.08.003

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AIM: To investigate the effect of platelet (PLT) on angiogenesis in hepatocellular carcinoma and the intervention effect of Cinobufagin (CBG). METHODS: Firstly, we screened the suitable co-incubation ratio of PLT and hepatocellular carcinoma cells, prepared conditioned medium, and determined the half inhibitory concentration of Cinobufagin; then, we set up a control group (human umbilical vein endothelial cells (EC)+conventional medium), a crosstalk group (EC+CM_HP (strip culture prepared by crosstalk of HUH7 and PLT)), and an intervention group (EC+CM_HP+CBG). The migration, tube-formation and sprouting capacity of EC and the level of vascular endothelial growth factor (VEGF) in co-cultured supernatant were evaluated by scratch assay, tube-formation assay, budding assay and ELISA assay. Western blot was used to detect the expression of VEGFR2 and p-VEGFR2, and reverse verification was performed with inhibitors. A subcutaneous transplantation tumour model of hepatocellular carcinoma in nude mice was established, with Model group, Model+CBG group and Model+Apa group. The collagen expression of the transplantation tumour was observed by Masson staining, and the expression levels of vascular endothelial markers CD31 and CD34 were detected by immunofluorescence. RESULTS: When PLT : HUH7=200, the activity of HUH7 was the strongest, and the crosstalk between HUH7 and PLT significantly promoted the proliferation of EC (P<0.01). Compared with Control group, the migration, tube-formation and budding ability of Crosstalk group were enhanced, and those of Intervention group were lower than those of Crosstalk group (P<0.01). The expression level of VEGF in the supernatant of Crosstalk group was higher than that of Control group, while that of Intervention group was lower than that of Crosstalk group (P<0.01). The expression level of p-VEGFR2 protein in Crosstalk group was significantly higher than that of Control group, but the expression level of Intervention group was lower than that of Crosstalk group (P<0.01). Large collagen fibre deposition was seen in the Model group, and CBG intervention significantly reduced collagen fibre deposition in the transplanted tumour tissues. CD31 and CD34 expression was present in the hepatocellular carcinoma transplanted tumour tissues in the Model group, and CBG intervention significantly reduced the expression of CD31 and CD34 in the liver cancer transplanted tumour tissues (P<0.01). CONCLUSION: PLT enhances angiogenesis in hepatocellular carcinoma, and CBG may inhibit its tube-forming ability via the VEGF/VEGFR2 pathway.

Icariin improves hypertensive renal fibrosis and injury through Cx32-Nox4 signaling pathway

WU Xiaoxue, YE Yiping, LEI Zhendong, ZHANG Zunjing, CHEN Wenling

2024, 29(8): 870-878. doi:10.12092/j.issn.1009-2501.2024.08.004

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AIM: To investigate the effect of icariin on renal fibrosis and injury in hypertension through Cx32-Nox4 signaling pathway. METHODS: Models of hypertensive nephropathy (HN) were established in spontaneously hypertensive rats (SHRs). The experiment was divided into 4 groups: normal control group (WKY rats), model group (SHR), icariin 10 mg·kg-1·d-1 group (icariin once daily), icariin 30 mg·kg-1·d-1 group (icariin once daily), n=10. The expression of fibrosis-related proteins was detected in vivo. NRK-52E cells exposed to AngII were selected to observe the effects of icariin on kidney injury. Extracellular matrix (ECM) levels, including α-smooth muscle actin (α-SMA), collagen I (Col-I) and fibronectin (FN) expression were measured by Western blot and immunohistochemistry. The expressions of oxidative stress markers including superoxide dismutase (SOD) and malondialdehyde (MDA) were determined by the test kit. RESULTS: Icariin reduced renal fibrosis in SHR rats in vivo. Icariin down-regulated the expression of α-SMA, FN, and Col-I and protected hypertension-damaged kidney tissue from progressive fibrosis (P<0.05). Icariin increased the total SOD activity and decrease the MDA level in kidney and serum of SHR rats (P<0.05). In addition, icariin increased the expression of Cx32 and decreased the expression of Nox4 in the kidneys of SHR rats (P<0.05). Icariin had a protective effect on AngII-mediated NRK-52E cell damage and fibrosis. CONCLUSION: Icariin can improve renal tubulointerstitial fibrosis and delay the progression of HN. Renal protection may be attributed to the regulation of oxidative stress mediated by the Cx32-Nox4 signaling pathway.

Improvement of insulin sensitivity in T2DM patients by glucagon-like peptide fusion protein

LIU Huan, LIU Yang, LUO Dan, GUO Lixin, LIU Dongyang

2024, 29(8): 879-886. doi:10.12092/j.issn.1009-2501.2024.08.005

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AIM: In order to quantitatively examine the improvement of insulin sensitivity (IS) in patients with type 2 diabetes mellitus (T2DM) when exendin-4-IgG4-Fc (E4F4) was given for 12 weeks, the present study was conducted to establish E4F4 population oral glucose minimal models based on the meal tolerance test (MTT) data of E4F4 pre- and post-dosing, and to analyze whether low-dose (2.7 mg) administration for 12 weeks significantly improved insulin sensitivity in patients with T2DM. METHODS: Blood glucose and insulin concentrations were collected among 16 subjects in the study who completed MTT before or after dosing. Nonlinear mixed-effects model construction for the population oral glucose minimal models was performed using NONMEN 7.2 software using pre- and post-dosing data, respectively. The insulin sensitivity parameters obtained from the models before and after the administration of the drug were statistically analyzed using GraphPad Prism 8.0. RESULTS: Nonparametric test of IS before and after dosing showed statistical difference (P=0.02), and insulin sensitivity after dosing was significantly higher than the baseline value before dosing. CONCLUSION: 12 weeks of low-dose E4F4 treatment in patients with type 2 diabetes mellitus resulted in an improvement in insulin sensitivity. This study provides a pharmacodynamic basis for the efficacy of this novel biologic.

Retrospective analysis on adverse drug reactions of four PD-1 inhibitors reported in literature

YU Xiao, ZHOU Yan, LI Qin, CHENG Xuefang

2024, 29(8): 887-898.

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AIM: To analyze the occurrence and clinical characteristics of adverse drug reactions (ADR) induced by four programmed cell death protein 1 (PD-1) inhibitors according to literature reports, and to provide reference for clinical safe medication. METHODS: PubMed, CNKI, and Wanfang, and other databases were searched to collect case reports of adverse reactions caused by four PD-1 inhibitors, including camrelizumab, sintilimab, toripalimab, and tislelizumab. RESULTS: A total of 105 eligible literature reports were retrieved from the databases at home and abroad (as of June 1, 2022), including 42 reports on camrelizumab with 47 patients, 29 reports on sintilimab with 30 patients, 21 reports on toripalimab with 24 patients and 13 reports on tislelizumab with 15 patients. Among them, there were 76 males (65.5%) and 40 females (34.5%), with a gender ratio of 1.9:1.0. The age range was between 29 to 84 years old, and the onset of ADR mainly occurred within 4 months after the first use of PD-1 inhibitors. Immune-related adverse reactions were mainly manifested as skin and its attachment (41 cases, 34.5%), endocrine system (25 cases, 21.0%), and cardiovascular system (22 cases, 18.5%). Most patients improved after symptomatic and?supportive?treatment. CONCLUSION: Immune-related adverse effects (irAEs) may occur at any time during treatment with the four PD-1 inhibitors, among these the skin system is most frequently affected, followed by the cardiovascular and endocrine systems. This suggests the importance of individualized drug administration and stringent control over indications in clinical practice. Close monitoring throughout immunotherapy is essential to minimize or prevent irAEs, thus ensuring patient safety in medication usage.

Retrospective study of the efficacy of vedolizumab in patients with inflammatory bowel disease

LI Peipei, WU Yue, ZHANG Xianzheng, ZHANG Lingling

2024, 29(8): 899-906. doi:10.12092/j.issn.1009-2501.2024.08.007

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AIM: To evaluate the efficacy and safety of vedolizumab in the treatment of inflammatory bowel disease. METHODS: The clinical data of 25 patients with inflammatory bowel disease (IBD) (13 ulcerative colitis (UC) and 12 Crohn's disease (CD)) treated with vedolizumab (VDZ) in the Anorectal department of our hospital from July 2020 to August 2023 were retrospectively collected. VDZ 300 mg was given intravenously at weeks 0, 2 and 6 to induce remission, and 300 mg was given intravenously every 8 weeks to maintain remission. The evaluation was carried out after 30 weeks of treatment. The primary efficacy indicators included clinical response rate, clinical remission rate, and endoscopic remission rate. The secondary efficacy indicators included nutritional status indicators (body weight (Wt), hemoglobin (HGB), albumin (ALB), hematocrit (HCT)), inflammation degree indicators (high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR)). All adverse reactions that occurred during VDZ treatment were recorded. RESULTS: The total clinical response rate of IBD patients treated with VDZ for 6 weeks and 14 weeks was 32% and 60%, respectively. The total clinical remission rate of IBD patients treated with VDZ for 14 weeks and 30 weeks was 16% and 36%, respectively. There was no significant difference in clinical response rate and clinical remission rate between UC and CD treated with VDZ (P>0.05). After 30 weeks of treatment, the body weight of UC patients was significantly increased, the levels of HCT%, ALB and HGB were significantly improved, and the level of ESR was significantly decreased. After 30 weeks of treatment, the body weight of CD patients increased significantly, and the inflammatory index hs-CRP, nutritional index HCT%, ALB and HGB levels were significantly improved. One patient had an increase in white blood cell count after the third infusion of VDZ, and no other adverse reactions occurred. CONCLUSION: As an induction and maintenance therapy for IBD patients, VDZ can alleviate intestinal inflammation, relieve clinical symptoms, improve nutritional status and improve quality of life of patients, with high safety.

Observation on the efficacy and safety of initial combined lipid-lowering strategy in patients with "very high-risk ASCVD" in cardiology outpatient department: real-world prospective cohort study

ZHAO Zhenyu, LI Yuan, GUO Yuxuan, MAO Xiaoxiao, MD Sayed Ali Sheikh, XIA Ke

2024, 29(8): 907-916. doi:10.12092/j.issn.1009-2501.2024.08.008

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AIM:To observe the efficacy and safety of combined lipid-lowering strategies in the initial stage of treatment in "very high-risk ASCVD" patients in cardiology outpatient clinics in a real-world prospective cohort study. METHODS: Patients with "very high-risk ASCVD" from January to June 2021 were consecutively enrolled and divided into three groups according to the actual lipid-lowering treatment strategies: Atorvastatin group; Atorvastatin combine with ezetimibe group; Atorvastatin combine with evolocumab group. The primary observation endpoints were the changes in LDL-C, Lp(a), and non-HDL-C after one month of treatment, and the secondary endpoints were the changes in TC, TG, HDL-C, Hs-CRP, and safety indicators. RESULTS: The efficacy of the combined lipid-lowering strategy in the initial stage of treatment was significantly better than that of the Atorvastatin group: LDL-C, Log ［Lp(a)］, non-HDL-C, TC significantly decreased (all P<0.05). Compared with the Atorvastatin combine with Ezetimibe group, LDL-C and Log ［Lp(a)］ decreased significantly in the Atorvastatin combine with Evolocumab group (P<0.05), and TC and TG had decreased insignificantly (P>0.05). When "LDL-C <1.4mmol/L or <1.8 mmol/L" is used as the standard for lipid-lowering compliance, the LDL-C compliance rates of the two groups of combined lipid-lowering treatments are higher than those of the atorvastatin single-drug group. The differences were all statistically significant (all P<0.05); the LDL-C compliance rate of the atorvastatin combined with evolocumab group was higher than that of the atorvastatin combined with ezetimibe group, and the differences were statistically significant (All P<0.05). When the reduction rate of "LDL dropped by more than 50%" alone or in combination were used as the standard, no one in the three groups could reach the standard.The liver aminotransferase levels had no significant changes among the 3 groups after treatment (all P>0.05). Myocardial enzyme isoenzyme (CK-MB) decreased among the 3 groups insignificantly (P>0.05). Compared with the Atorvastatin group, the blood sugar (BS) of the two combined lipid-lowering groups decreased significantly (P<0.05); The BS of the Atorvastatin + ezetimibe group significantly decreased than that of Atorvastatin combine with Evolocumab group (P<0.05). CONCLUSION: The lipid-lowering effect and LDL-C compliance rate of patients with "very high-risk ASCVD" in the cardiology outpatient department after 1 month of combined lipid-lowering treatment were better than those of the atorvastatin monotherapy group.When LDL-C <1.4 mmol/L or <1.8 mmol/L is the lipid-lowering target, the LDL-C compliance rate after 1 month of treatment in the atorvastatin combined with evolocumab group is higher than that of the combined atorvastatin and zetamibu group. When the "LDL drop by more than 50%" is used as the standard for lipid lowering, it is difficult to reach the standard within 1 month. Outpatient "very high-risk ASCVD" patients were treated with initial combined lipid-lowering therapy for 1 month without adverse reactions. The initial combined lipid-lowering strategy can be used for patients with "very high-risk ASCVD" in cardiology outpatient clinics who need to achieve LDL-C values early. Atorvastatin combined with evolocumab strategy can be recommended for those patients who require LDL-C<1.4 mmol/L or <1.8 mmol/L within one month.

Research progress of miRNA in ulcerative colitis

LIU Xuan, FENG Cuijuan, WANG Yiqiang, LI Fang

2024, 29(8): 917-929. doi:10.12092/j.issn.1009-2501.2024.08.009

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Ulcerative colitis (UC) is a chronic immune-mediated disease characterized by diffuse mucosal inflammation and clinical symptoms of abdominal pain, diarrhea, mucopurulent bloody stool and tenesmus. Due to its complex etiology, difficult treatment and poor prognosis, UC has been listed as one of the modern refractory diseases by the World Health Organization. MicroRNAs (microRNAs) regulate various biological processes such as cell growth, differentiation, and development by regulating gene expression. Studies have shown that miRNA is involved in the pathogenesis of UC through various pathways such as intestinal mucosal barrier homeostasis disorder, intestinal flora imbalance and excessive differentiation of immune cells, and is expected to become a new target for clinical treatment of UC. In order to better understand the role of miRNA in the pathogenesis of UC and provide new research directions for the treatment of UC, this article reviews the correlation between miRNA and the pathogenesis of UC, the potential of miRNA as a biomarker of UC, and the treatment strategies of miRNA in UC in recent years.

Research progresses of nonsense-mediated mRNA decay in tumorigenesis and cancer therapy

WANG Yuhui, WANG Jingpeng, CHEN Bei, WANG Yaru, LI Tangliang

2024, 29(8): 930-936. doi:10.12092/j.issn.1009-2501.2024.08.010

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Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional regulatory mechanism in eukaryotic cells. NMD can recognize and degrade abnormal transcripts containing premature termination codons (PTC) to prevent the translation of C-terminal truncated proteins. Furthermore, NMD could degrade a subset of normal gene transcripts and thus fine-tune gene expression. NMD is essential for cell fate determination, stress response, as well as animal development. In this review, we briefly discussed the functional and molecular mechanisms of NMD pathway activation and inhibition in tumorigenesis, cancer progression and therapy. Current studies indicate that NMD factor mutations can lead to a variety of human tumors. Interestingly, inhibition of NMD factors can activate DNA damage response and inhibit the expression of oncogenic factors, thereby killing cancer cells. This review may provide new perspectives for the biological mechanism and therapeutic strategy of human tumors.

Advances in clinical research of CAR-T immunotherapy for systemic rheumatic diseases

LI Zhi, ZHANG Mengying, ZHU Chuanmiao, MAO Li, PENG Hui

2024, 29(8): 937-946. doi:10.12092/j.issn.1009-2501.2024.08.011

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Systemic rheumatic disease is a kind of autoimmune disease which is caused by the dysfunction of autoimmune cells and the damage of multiple systems and organs. Traditional immunosuppressants play an important role in the treatment of systemic rheumatic diseases, but there are still a considerable number of refractory systemic rheumatic diseases that do not respond well to traditional immunosuppressant therapy, and new therapeutic methods need to be explored. Chimeric antigen receptor T cell therapy (CAR-T) immunotherapy was initially used for the treatment of malignant hematological diseases and has shown good efficacy. Recently,CAR-T immunotherapy has also achieved remarkable efficacy in refractory systemic lupus erythematosus. It brings new hope for the treatment of systemic rheumatic diseases. This article summarizes the progress of clinical application of CAR-T immunotherapy in systemic rheumatic diseases in recent years, aiming to enhance clinicians' cognition of CAR-T immunotherapy and promote the further development of CAR-T immunotherapy in systemic rheumatic diseases.

Progress on anti-tumor mechanisms of Ganoderma lucidum active ingredients

LV Yujiao, ZHOU Shuting, WANG Lina, SHEN Mingmei, LIU Yongchao

2024, 29(8): 947-954. doi:10.12092/j.issn.1009-2501.2024.08.012

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Malignant tumors are one of the main causes of death from chronic diseases in China, and their incidence and mortality rates show an increasing trend year by year. Advanced non-surgical treatment of malignant tumors is an important means of improving patients' prognosis and enhancing their quality of life. The traditional Chinese medicine Ganoderma lucidum has anti-tumor effects and plays a role in the treatment of many malignant tumors. In this paper, a systematic review of the effects of Ganoderma lucidum active ingredients on tumors has been conducted at home and abroad in the past five years to explore the anti-tumor mechanism of Ganoderma lucidum active ingredients and to lay a theoretical foundation for the application of Ganoderma lucidum active ingredients in clinical practice.

Research progress of molecular docking in screening anti-cervical cancer drugs

WANG Dan, ZHANG Wenyan, LUO Renjie, CHEN Yuanjing, HAN Xue, QU Bo, FENG Shifang, NIE Xiazi, LIU Huiling

2024, 29(8): 955-960. doi:10.12092/j.issn.1009-2501.2024.08.018

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Cervical cancer is one of the most common gynecological malignant tumors,the five-year survival rate decreased significantly in the case of lymph node metastasis and distant metastasis,so the development of new anti-cervical cancer drugs is of great significance for the treatment of cervical cancer.Molecular docking technology is one of the most commonly used research methods in computer aided drug design,which is widely used in screening the effective components of drugs, finding the targets of drugs acting on tumors and exploring the mechanism of antineoplastic drugs. This paper reviews the molecular docking technology in the screening of anti-cervical cancer drugs,the determination of anti-tumor targets and the mechanism of anti-cervical cancer,in order to provide more sufficient theoretical basis for the screening of anti-cervical cancer drugs and new drug research and development.

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