Chinese Journal of Clinical Pharmacology and Therapeutics

Model informed precision dosing: China expert consensus report

JIAO Zheng, LI Xingang, SHANG Dewei, DONG Jing, ZUO Xiaocong, CHEN Bing, LIU Jianmin, PAN Yan, ZHOU Tianyan, ZHANG Jing, LIU Dongyang, LI Lujin, FANG Yi, MA Guangli, DING Junjie, ZHAO Wei, CHEN Rui, XIANG Xiaoqiang, WANG Yuzhu, GAO Jianjun, XIE Haitang, HU Pei, ZHENG Qingshan

2021, 26(11): 1215-1228. doi:10.12092/j.issn.1009-2501.2021.11.001

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Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.

Effect of lienal polypeptide injection on primary immune thrombocytopenia

YUE Zhaorong, XIE Fei, WANG Xin, LI Hongyu

2021, 26(11): 1229-1236. doi:10.12092/j.issn.1009-2501.2021.11.002

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AIM: To explore the effect of lienal polypeptide injection (LPI) on platelet production in ITP model mice with primary immune thrombocytopenia. METHODS: SPF Kunming mice were divided into groups by random number table method, and the ITP model of mice was induced by intraperitoneally injected of rabbit anti-mouse platelet serum APS every other day. At the set time, blood was collected through caudal vein to detect the changes in the number of platelets, red blood cells and white blood cells in each group. Meanwhile, the thymus and spleen indexes were calculated. Megakaryocytes were classified and counted by means of bone marrow smear. Finally, the expression levels of TPO, SCF, IL-3, IL-6, IL-11, β-TG, TGF-β1 and PF-4 in serum were detected by ELISA. RESULTS: LPI significantly increased platelets count in ITP model mice, but had no effect on red blood cells and white blood cells. Thymus and spleen index decreased significantly. The number of megakaryoblasts and thrombocytopenia megakaryocytes in the bone marrow of mice increased, but the number of promegakaryocytes, granular megakaryocytes and naked megakaryocyte did not change significantly. Serum sytokines SCF, IL-3 and IL-6 were significantly increased, while PF-4 was decreased significantly. CONCLUSION: LPI may increase the platelet count in ITP mice by up regulating the levels of IL-3, IL-6, SCF and down regulating the level of PF-4, which has guiding significance for clinical promotion application of LPI.

Protective effect and mechanism of lycium barbarum polysaccharides on diabetic renal injury

ZHANG Na, TANG Futian

2021, 26(11): 1237-1243. doi:10.12092/j.issn.1009-2501.2021.11.003

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AIM: To study the protective effect and mechanism of Lycium barbarum polysaccharide (LBP) on diabetic kidney injury in rats. METHODS: Intraperitoneal injection of streptozotocin (STZ) to establish a rat model of diabetes (DM). The rats were divided into control group, diabetes group, LBP (60 mg/kg) group and LBP (30 mg/kg) group. The LBP group was given LBP by gavage once a day for 12 weeks. Determination of rat fasting blood glucose level, blood creatinine (Scr), urea nitrogen (BUN), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) content. Calculate relative kidney mass, observe changes in kidney tissue morphology, and determine superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activity, and glutathione (GSH) in kidney tissue, malondialdehyde (MDA) content, nuclear factor-кB (NF-кB) subunit p65, intercellular adhesion molecule-1 (ICAM-1) andmonocyte chemotactic protein-1 (MCP-1) expression. RESULTS: Compared with the control group, the blood glucose of rats in the diabetic group was significantly increased (≥16.7 mmol/L), the content of Scr, BUN, CRP, IL-6, and TNF-α in the serum increased, the content of MDA in the kidney tissue increased, and the content of GSH increased And GSH-Px, CAT, SOD activity decreased, NF-кB subunit p65, MCP-1 and ICAM-1 expression levels increased. Compared with the diabetes group, LBP can reduce blood glucose in diabetic rats, reduce the serum levels of Scr, BUN, CRP, IL-6, and TNF-α, reduce the content of MDA in kidney tissue, increase the content of GSH, GSH-Px, CAT, SOD, and down-regulate the expression levels of NF-кB subunit p65, MCP-1 and ICAM-1. CONCLUSION: LBP has a significant protective effect on diabetic kidney injury, and its mechanism of action may be related to the improvement of blood glucose, reduction of renal oxidative stress and reduction of inflammatory reaction in diabetic rats.

Gastrodin combined with dexamethasone protects H9C2 cell from injury induced by oxygen-glucose deprivation

WU Wei, LI Guangpeng, ZHANG Jiangbo, KONG Lingyu, CAI Junyan, YANG Feiyun

2021, 26(11): 1244-1249. doi:10.12092/j.issn.1009-2501.2021.11.004

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AIM: To investigate the role and possible mechanism of gastrodin combined with dexamethasone in myocardial cell injury induced by oxygen-glucose deprivation. METHODS: Oxygen-glucose deprivation (OGD) model was established. The cells were divided into 5 groups: normal control group, OGD group, DEX group, GAS group and DEX+GAS group. The activity of myocardial cells was detected by CCK-8 test in each group. The activity of LDH was detected by colorimetry in each group. The apoptosis of myocardial cells was detected by TUNEL method in each group. The ELISA assay was used to detect the inflammatory factors in culture medium of myocardial cells in each group. Western blot was used to detect the expression of Notch1, Bax, Bcl-2 and Beclin1 in myocardial cells in each group.RESULTS: The results showed that GAS combined with DEX could significantly increase the activity of myocardial cells and decrease the apoptosis, reduce production of TNF-α, IL-6, IL-1β and promote production of IL-10, decrease the release of LDH significantly of myocardial cells induced by OGD. The results of Western blot showed that GAS combined with DEX increased the expression of Notch1, Bcl-2 and autophagy-related gene Beclin1, but decreased the expression of Bax of myocardial cells induced by OGD. CONCLUSION: The combination of GAS and DEX may promote autophagy and increase cell activity, inhibit apoptosis and inflammatory reaction by activating Notch signaling pathway, thereby reducing OGD-induced myocardial cells damage.

Relationship between gene polymorphism of inhaled glucocorticosteroids budesonide and efficacy in asthma

LI Jing, Ma Lijuan, YUAN Yuan, WANG Jie, YU Changzhi, ZHAO Jun

2021, 26(11): 1250-1258. doi:10.12092/j.issn.1009-2501.2021.11.005

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AIM: To investigate the relationship among the rs37973 polymorphism of glucocorticoid induced transcription factor 1 (GLCCI1) gene, the rs1876828 polymorphism of corticotropin-hormone receptor 1 (CRHR1) gene, the rs28364072 polymorphism of Fc fragment of IgE receptor II (FCER2) gene and the response to inhaled corticosteroids (ICS) budesonide in patients with asthma. METHODS: 152 blood samples of patients with asthma were collected. The DNA were studied by blood samples. Fluorescence in situ hybridization method was used to detect the polymorphism of GLCCI1, CRHR1, FCER2. Lung function index of the ICS before and after treatment, such as forced vital capacity (FVC), first second forced breath volume (FEV1) and first second forced breath volume of forced lung (FEV1/FVC%), and Eosinophil count (EOS) et al. were collected. The change value of FVC, FEV1, FEV1/FVC and their improvement rate were calculated. The relationship between GLCCI1, CRHR1 and FCER2 gene polymorphism and altered lung function before and after treatment in asthma patients was analyzed. RESULTS: There was significant difference between Han and Uyghur asthmatic patients in the distribution frequency of GLCCI1 and FCER2 genotypes. No CRHR1 AA genotype was found in the study population, but there was significant difference between Han and Uyghur patients in the distribution frequency of CRHR1 GG and GA genotype. The difference of FVC and the improvement rate of FVC in GLCCI1 AA type and GG type patients was similar before and after treatment (P>0.05), but the difference of FVC and the improvement rate of FVC in AG type patients were significantly increased compared with GG type patients' (P<0.05). The difference of FEV1/FVC before and after drug treatment in FCER2 AA and AG genotype was similar (P>0.05), but the difference of FEV1/FVC before and after ICS treatment in FCER2 AA and AG genotype was significantly higher than that in GG (P<0.05). The difference of FEV1/FVC before and after treatment in patients with CRHR1 GA genotype was more significant than that with GG genotype (P<0.05). Han and Uygur patients with FCER2 AA and GG genotype had similar changes in pulmonary function indexes after treatment (P>0.05), while Uygur patients with AG genotype had significantly increased in FEV1 improvement rate, FEV1/FVC difference and FEV1/FVC improvement rate after ICS treatment compared with Han patients (P<0.05).CONCLUSION: There was relevance among GLCCI1 rs37973, CRHR1 rs1876828, FCER2 rs28364072 gene polymorphism and lung function in inhaled corticoids budesonide treatment, which may be a genetic indicator to predict the efficacy of inhaled glucocorticoids in asthma patients.

Distribution of gene polymorphism in folate metabolism pathway and its effect on serumhomocysteine concentration

YANG Chunyan, ZHANG Wen, WANG Peipei, PENG Jing, JIANG Jia, SONG Jing, LIU Jun, LI Yueran, YANG Kui, WANG Sheng, XU Zhenyu, LUAN Jiajie

2021, 26(11): 1259-1264. doi:10.12092/j.issn.1009-2501.2021.11.006

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AIM: To study the polymorphism distribution of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes and their influence on serum homocysteine (Hcy) concentration. METHODS: A total of 148 patients diagnosed with ischemic stroke from November 2020 to February 2021 in Yijishan Hospital of Wanan Medical College were selected for the study, and patients were typed for MTHFR 677C/T and MTRR 66A/G genes using fluorescent staining in situ hybridization technique. Serum Hcy concentrations were measured in 21 patients using a circulating enzyme assay. The distribution of MTHFR 677C/T and MTRR 66A/G gene polymorphisms were analyzed, and the differences in serum Hcy concentrations between patients with different genotypes were compared. RESULTS: The mutation rates of MTHFR 677C/T and MTRR 66A/G genes were 42.57% and 26.01%, respectively, and no significant differences in gene distribution frequencies were observed between men and women (P>0.05). The mean Hcy serum concentration was (16.04±4.34) μmol/L in 21 patients, including 8 patients (38.10%) with <15 μmol/L and 13 patients (61.90%) with ≥15 μmol/L. The Hcy serum concentrations in patients with different genotypes of MTHFR were TT (18.91±5.34) μmol/L, CT (14.38±1.84) μmol/L and CC (13.58±2.86) μmol/L, respectively, and were statistically different (P<0.001). Serum Hcy concentrations in patients with different genotypes of MTRR were not statistically different (P>0.05). CONCLUSION: MTHFR gene polymorphisms can affect serum Hcy concentrations. The MTHFR genotyping can be considered for individualized folic acid supplement. This conclusion should be further verified by expanding the clinical sample size.

Population pharmacokinetics/pharmacodynamics of tigecycline in the treatment of different infectious diseases

LI Wenchao, BAI Xiangrong, LI Xiaoling, JIANG Dechun

2021, 26(11): 1265-1272. doi:10.12092/j.issn.1009-2501.2021.11.007

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AIM: To provide reference for the clinical application of tigecycline and subsequent population pharmacokinetic-pharmacodynamics study in the future. METHODS: The Chinese and English keywords of "Tigecycline", "population pharmacokinetics", "population pharmacokinetic model", "pharmacodynamics" or "Tigecycline" pharmacokinetics "were used to search the relevant references published from the time of self-establishment to June 1, 2021 in PubMed, China Knowledge Infrastructure, Wanfang and other databases. The research progress of population pharmacokinetics and pharmacodynamics of tigecycline was reviewed. RESULTS & CONCLUSION: A total of 73 relevant references were retrieved, including 8 tigecycline PPK studies and 7 tigecycline PK/PD studies. At present, tigecycline PPK models had been established in patients with complex intra-abdominal infections, skin and skin and soft tissue infections, community-acquired pneumonia, nosocomial pneumonia, septic shock and other severe infections, including 8 two-compartment models. The main covariates affecting tigecycline plasma clearance were weight-related, liver function and renal function-related parameters. Body weight was also an important factor influencing the apparent volume of distribution. The effect of different disease types on the pharmacokinetics of tigecycline was different, and it needed to be considered and selected in combination with the specific circumstances of patients when formulating clinical dosing regimens. Pharmacodynamics studies should consider not only the type of disease, pathogens and patient factors themselves, but also the characteristics of atypical nonlinear plasma protein binding of tigecycline. In order to accurately understand the efficacy of different dose regimens, it was necessary to monitor the therapeutic drugs of tigecycline.

Pharmacokinetics and bioequivalence evaluation of ciprofloxacin tablets in healthy Chinese subjects under fasting and fed conditions

WANG Lu, RUAN Zourong, ZHANG Kaiwen, CHEN Jing, YANG Dandan, SHAO Rong, JIANG Bo

2021, 26(11): 1273-1278. doi:10.12092/j.issn.1009-2501.2021.11.008

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Analysis of the clinical efficacy of three kinds of Chinese patent medicines assisting tacrolimus in the treatment of nephrotic syndrome

ZHONG Lingjun, HU Linlin, HE Jie, SHAO Hua

2021, 26(11): 1285-1291. doi:10.12092/j.issn.1009-2501.2021.11.010

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