AIM:To establish a physiological-based pharmacokinetic(PBPK)model of ertapen-em in elderly patients with chronic kidney disease,and to analyze the pharmacokinetic/pharmacody-namic index f％ T＞MIC at different doses.METH-ODS:The physicochemical properties and pharma-cokinetic characteristics of ertapenem were collect-ed by reviewing the literature and databases,and a healthy adult model was established in PKSim? software,and then extrapolated to the PBPK model of the elderly.The clinical pharmacokinetic re-search data were used to optimize and validate the model,and the mean folding error(MFE)was used as the index to evaluate the prediction perfor-mance of the model.The final model was used to simulate the in vivo exposure of elderly patients with chronic kidney disease after administration,and the pharmacokinetic/pharmacodynamic index of commonly used clinical dosing regimens was an-alyzed,and the recommended dosing regimens were given.RESULTS:The MFE of the area under the curve(AUC0-t),peak concentration(Cmax)and peak time(Tmmax)predicted by the established PBPK model of ertapenem in adults were 0.92,0.79 and 1.02,respectively,and the predicted value of the optimized PBPK model of ertapenem in the elderly was also consistent with the observed value of 0.5＜MFE＜2 standards,all of which have good predictive performance.With f％ T＞MIC greater than 40％as the drug efficacy target,the minimum inhibitory concentration(MIC)is 0.5-1 μg/mL for sensitive bacteria,and elderly patients with chronic kidney disease can consider reducing the drug dose as ap-propriate.CONCLUSION:The PBPK model of ertap-enem in elderly patients with renal insufficiency has been successfully established,and the model has good prediction performance and provides a reference for clinical personalized medication in el-derly patients with renal insufficiency.

AIM:To establish a physiological-based pharmacokinetic(PBPK)model of ertapen-em in elderly patients with chronic kidney disease,and to analyze the pharmacokinetic/pharmacody-namic index f％ T＞MIC at different doses.METH-ODS:The physicochemical properties and pharma-cokinetic characteristics of ertapenem were collect-ed by reviewing the literature and databases,and a healthy adult model was established in PKSim? software,and then extrapolated to the PBPK model of the elderly.The clinical pharmacokinetic re-search data were used to optimize and validate the model,and the mean folding error(MFE)was used as the index to evaluate the prediction perfor-mance of the model.The final model was used to simulate the in vivo exposure of elderly patients with chronic kidney disease after administration,and the pharmacokinetic/pharmacodynamic index of commonly used clinical dosing regimens was an-alyzed,and the recommended dosing regimens were given.RESULTS:The MFE of the area under the curve(AUC0-t),peak concentration(Cmax)and peak time(Tmmax)predicted by the established PBPK model of ertapenem in adults were 0.92,0.79 and 1.02,respectively,and the predicted value of the optimized PBPK model of ertapenem in the elderly was also consistent with the observed value of 0.5＜MFE＜2 standards,all of which have good predictive performance.With f％ T＞MIC greater than 40％as the drug efficacy target,the minimum inhibitory concentration(MIC)is 0.5-1 μg/mL for sensitive bacteria,and elderly patients with chronic kidney disease can consider reducing the drug dose as ap-propriate.CONCLUSION:The PBPK model of ertap-enem in elderly patients with renal insufficiency has been successfully established,and the model has good prediction performance and provides a reference for clinical personalized medication in el-derly patients with renal insufficiency.

[摘 要] 目的：探讨IL-22/IL-22受体A1（IL-22RA1）通路在口腔鳞状细胞癌（OSCC）恶性进展中的作用及其机制。方法：利用GEO数据库和免疫组化法分析IL-22RA1在OSCC组织及配对癌旁组织中的表达水平，采用组织芯片免疫组化法检测并分析IL-22RA1表达水平与OSCC患者临床病理特征的关系，通过EBI ArrayExpress数据库分析IL-22RA1表达水平与患者预后的关系。采用免疫荧光法检测IL-22和IL-22RA1在OSCC组织中表达水平并分析两者间的相关性。用RNA干扰技术敲减OSCC细胞WSU-HN4和CAL27的IL-22RA1表达，用qPCR法验证敲减效率。采用克隆形成实验、Transwell小室法分别检测IL-22对阴性对照（siNC）组和IL-22RA1敲减（siIL-22RA1）组OSCC细胞克隆形成及迁移能力的影响，WB法检测IL-22对OSCC细胞IL-22RA1表达水平及STAT1、STAT3和ERK1/2磷酸化水平的影响。结果：OSCC组织中IL-22RA1 mRNA的表达水平显著高于癌旁组织（P<0.05）。IL-22RA1表达水平与OSCC患者的肿瘤大小（P<0.05）、淋巴结转移（P<0.01）及预后不良（P<0.05）有关联。OSCC组织中的IL-22和IL-22RA1表达水平无明显关联，IL-22对OSCC细胞IL-22RA1表达无影响（均P>0.05）。IL-22可显著增强OSCC细胞的克隆形成和迁移能力（均P<0.01），并可激活OSCC细胞的STAT1、STAT3及ERK1/2信号分子；敲减OSCC细胞的IL-22RA1后，IL-22则无法发挥上述作用。结论：IL-22/IL-22RA1可通过调控细胞增殖和迁移促进OSCC的生长和转移，其下游机制可能是激活ERK1/2-STAT1/3信号通路。

A combined radiation-wound injury refers to a radiation injury combined with a traumatic wound, with the characteristics of repeated ulceration and a long and difficult healing process, which is a focus in the field of research on difficult-to-heal wounds. To research combined radiation-wound injuries, the establishment of animal models is a key part, and appropriate animal models are a guarantee of reliable experimental results. This review summarizes the current research progress on various animal models of combined radiation-wound injuries in terms of radiation types, animal species, and injury types and location, aiming to provide a scientific basis for establishing standardized animal models, studying injury mechanisms, and evaluating prevention and treatment efficacy for combined radiation-wound injuries.

Objective:To investigate the expulsion rate of GyneFix postpartum intrauterine device (PPIUD) placed immediately after cesarean section within one year and its influencing factors.Methods:A prospective cohort study was conducted. Women who volunteered to use a GyneFix PPIUD placed immediately after cesarean section (within 10 min after placenta delivery) for postpartum contraception were recruited from September 2017 to November 2020. The relevant information was collected through questionnaires before, during and 24 h after cesarean section. Outpatient follow-up was conducted at 42 d, 3 months, 6 months and 12 months after delivery to obtain information on expulsion of GyneFix PPIUD and unwanted pregnancy. Life table and Cox regression model were used to analyze the cumulative expulsion rate and related influencing factors.Results:A total of 470 subjects were recruited and 461 (98%) subjects were eligible for this study. The cumulative expulsion rate of GyneFix PPIUD within one year after cesarean section was 8.4% (95% CI: 7.0%-9.8%). Multivariate Cox regression analysis showed that women aged >35 years had significantly lower risk of PPIUD expulsion than those aged <25 years ( HR=0.16, 95% CI: 0.04-0.64). The risk of GyneFix PPIUD was not statistically significantly associated with cesarean section history and breastfeeding mode (all P>0.05). Nevertheless, this risk was statistically significant between hospitals. The Pearl index of contraceptive failure of the device was 2.37 (95% CI: 1.09-4.50) per 100 person-years. The rate of contraceptive failure was not associated with maternal age, breastfeeding mode, and history of cesarean delivery (all P>0.05). Conclusion:The one-year cumulative expulsion rate of GyneFix PPIUD placed immediately after cesarean section is 8.4%. Young mothers were at a higher risk of expulsion than their older counterparts. The device users should be counseled regarding the signs of expulsion. In case of expulsion, women should be offered reinsertion or other contraceptive methods. The training of service skills of GyneFix PPIUD should be strengthened in order to mitigate the risk of the device expulsion.

Objective:To investigate the expulsion rate of GyneFix postpartum intrauterine device (PPIUD) placed immediately after cesarean section within one year and its influencing factors.Methods:A prospective cohort study was conducted. Women who volunteered to use a GyneFix PPIUD placed immediately after cesarean section (within 10 min after placenta delivery) for postpartum contraception were recruited from September 2017 to November 2020. The relevant information was collected through questionnaires before, during and 24 h after cesarean section. Outpatient follow-up was conducted at 42 d, 3 months, 6 months and 12 months after delivery to obtain information on expulsion of GyneFix PPIUD and unwanted pregnancy. Life table and Cox regression model were used to analyze the cumulative expulsion rate and related influencing factors.Results:A total of 470 subjects were recruited and 461 (98%) subjects were eligible for this study. The cumulative expulsion rate of GyneFix PPIUD within one year after cesarean section was 8.4% (95% CI: 7.0%-9.8%). Multivariate Cox regression analysis showed that women aged >35 years had significantly lower risk of PPIUD expulsion than those aged <25 years ( HR=0.16, 95% CI: 0.04-0.64). The risk of GyneFix PPIUD was not statistically significantly associated with cesarean section history and breastfeeding mode (all P>0.05). Nevertheless, this risk was statistically significant between hospitals. The Pearl index of contraceptive failure of the device was 2.37 (95% CI: 1.09-4.50) per 100 person-years. The rate of contraceptive failure was not associated with maternal age, breastfeeding mode, and history of cesarean delivery (all P>0.05). Conclusion:The one-year cumulative expulsion rate of GyneFix PPIUD placed immediately after cesarean section is 8.4%. Young mothers were at a higher risk of expulsion than their older counterparts. The device users should be counseled regarding the signs of expulsion. In case of expulsion, women should be offered reinsertion or other contraceptive methods. The training of service skills of GyneFix PPIUD should be strengthened in order to mitigate the risk of the device expulsion.

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus.The active endostatin fragment of PEPO6 directly targets tumor cells and exerts an antitumoral effect.However,little is known about the kinetics and degradation products of PEP06 in vitro or in vivo.In this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage products.PEP06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06.We identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino acids.The metabolites were C and N terminal truncated products of PEP06.The structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites.We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

Objective:To explore the disturbance of metal element balance in mice after exposure to radon.Methods:Mice were randomly divided into control group, radon exposure of 30 WLM group, 60 WLM group and 120 WLM groups, with 10 mice in each group. After radon exposure with the cumulative dose, the lung function of mice was detected by a non-invasive pulmonary function testing instrument. Mice blood was taken from eyeballs. The lungs, heart, liver, kidney and spleen were also collected. HE staining was used to observe the pathological changes of lung tissue. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the content of metal elements, including essential trace elements in the body: chromium (Cr), molybdenum (Mo), cobalt (Co), selenium (Se), copper (Cu), zinc (Zn), manganese (Mn), nickel (Ni), and potentially toxic elements: arsenic (As), tin (Sn), lead (Pb), aluminum (Al), mercury (Hg), cadmium (Cd), and silver (Ag).Results:Compared with the control group, lung ventilation function of the radon-exposed mice was decreased, alveolar structure was destroyed, and the contents of pulmonary metal elements Cr, Al, Pb, Sn( F=0.34, 0.66, 3.14, 1.16, P<0.05) and essential trace elements Mn, Cr, Zn, and Mo in the blood were decreased( F=0.65, 1.44, 0.97, 2.08, P<0.05), while the elements of Cu, Mo, Se and As in the lungs were increased( F=1.31, 1.26, 0.81, 2.04, P<0.05), and the element contents in other tissues also fluctuated. Conclusions:Inhalation of a certain cumulative dose of radon can reduce the lung ventilation function of mice and induce lung inflammation, as well reduce the content of essential trace elements in the lung and blood so that the content of metal elements in the body fluctuates.

A rapid, sensitive and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the simultaneous determination of yogliptin and its metabolite in Wistar rat plasma. Linagliptin and dexamethasone were chosen as the internal standards of yogliptin and its metabolite, (R)-8-(3-hydroxypiperidine- -yl)-7-(but-2-yn-1-yl)-1-((5-fluorobenzo[d]thiazol-2-yl)methyl)-3-methyl- H-purine-2, 6 (3H, 7H)-dione, respectively. After a simple protein precipitation using acetonitrile as the precipitating solvent, both analytes and ISs were separated on a Grace Altima HP C18 column (2.1 mm x 50 mm, 5 microm) with gradient elution using methanol (containing 0.1% formic acid, 4 mmol x L(-1) ammonium acetate)-0.1% formic acid (containing 4 mmol x L(-1) ammonium acetate) as the mobile phase. A chromatographic total run time of 4.4 min was achieved. Mass spectrometric detection was conducted with electrospray ionization under positive-ion and multiple-reaction monitoring modes. Linear calibration curves for yogliptin and its metabolite were over the concentration range of 0.5 to 500 ng x mL(-1) with a lower limit of quantification of 0.5 ng x mL(-1). The intra- and inter- assay precisions were all below 14%, the accuracies were all in standard ranges. The method was used to determine the concentration of yogliptin and M1 in Wistar rat plasma after a single oral administration of yogliptin (27 mg x kg(-1)). The method was proved to be selective, sensitive and suitable for pharmacokinetic study of yogliptin and M1 in Wistar rat plasma.

Healthy Beagle dogs were administrated with batroxobin by intravenous infusion at high, medium and low doses. The study of pharmacodynamics and pharmacokinetics was intended to clarify the relevance of them and provided strong evidence for clinical use of batroxobin. The blood samples were collected after injection based on the time schedule and samples were tested by ELISA method to get the concentration of batroxobin. At the same time, changes of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimmer were tested. The results showed that the concentration of D-D increased significantly after administration compared with that of before administration. The main pharmacokinetic parameters were as follows: t1/2 were (2.27 +/- 0.42) h, (10.65 +/- 2.19) h and (11.01 +/- 3.51) h; C(max) were (11.9 +/- 1.72) ng x mL(-1), (154.53 +/- 12.38) ng x mL(-1) and (172.14 +/- 47.33) ng x mL(-1); AUC(last) were (29.38 +/- 3.69) ng xh x mL(-1), (148.43 +/- 72.85) ng x h x mL(-1) and (599.22 +/- 359.61) ng x h x mL(-1). The elimination of batroxobin was found to be in accord with linear kinetics characteristics. The results of pharmacodynamics showed that D-dimmer level increased significantly after the administration of batroxobin, which was similar with the changes of batroxobin plasma concentration. Simultaneously, Fib concentrations in Beagle dog blood decreased significantly after the iv administration of batroxobin, while recovered to base level after 48 hours. PT, TT and APTT significantly became longer after administration, which returned to normal level after 48 hours. Especially, the D-dimmer levels and the batroxobin concentration in plasma after intravenous infusion of the drug were synchronized in Beagle dogs. Changes between PD/PK results had obvious correlation, and the D-dimmer levels in plasma can be one of the important monitoring indicators of batroxobin in thrombolytic medication.