透析液电导率对肾纤维化终末期透析患者电解质平衡的重要性

目的：分析透析液中各主要离子对肾纤维化终末期透析患者的影响作用,探讨透析机对透析液电导率进行实时监测的意义。方法：通过对透析液系统的不同混合比例稀释进行监测,对透析机温度补偿系统进行检测。分析透析液浓度监测部分的工作原理及计算方法。结果：透析液温度补偿及电导度传感器均对血透机透析液电导率的精准性起到至关重要的作用。结论：通过分析、论述透析液中各离子对肾病透析患者的作用与影响,阐明透析液质量的重要性,以及透析机对透析液浓度进行实时监测的必要性。     

2012年安丘市两乡镇克山病病情监测分析

目的观察克山病病情及发病相关因素的动态变化,为防治科研提供科学依据。方法2012年选择安丘市克山病病区吾山镇张家南庄村和官庄镇挑河村为调查点,对全村常住居民进行临床查体、描记心电图和x线胸部摄片,同时对病村经济情况、人均占有粮食量进行调查,并对受检人群头发以及小麦、玉米等食物和土壤硒水平进行采样检测。结果吾山镇张家南庄村常住居民836人,人均年收人约4200元,粮食供应充足;调查430人,检出异常心电图150人,心电图异常率为34．88％,未检出克山病病例;对头发、小麦、玉米、土壤进行硒含量（mg／kg）检测,依次为（0．361±0．062）、（0．026±0．004）、（0．022±0．003）、（0．116±0．015）。官庄镇挑河村常住人口658人,人均年收入约7400元,粮食供应允足;调查420人,检出异常心电图90人,心电图异常率为23．10％,未检出克山病病例;对头发、小麦、玉米、土壤进行硒含量（mg／kg）检测,依次为（0．359±0．057）、（0．023±0．013）、（0．018±0．011）、（0．136±0．022）。两监测点的头发、小麦、乇米、土壤硒含量差异均无统计学意义（P均〉0．05）。结论安丘市近20多年来克山病病情无明显变化,一直处于低发病水平,无新发克山病病例,本次监测也未检出新发病例。     

剖宫产瘢痕妊娠患者甲氨蝶呤胎囊注射联合B超监测下清宫术的疗效分析

目的 探究甲氨蝶呤胎囊注射联合B超监测下清宫术治疗剖宫产瘢痕妊娠患者的临床效果。方法 回顾性分析2014年10月至2017年10月安钢总医院收治的87例剖宫产瘢痕妊娠患者临床资料,按治疗方案不同分为对照组（n=43）与试验组（n=44）。对照组患者单纯采取甲氨蝶呤胎囊注射治疗,试验组患者采取甲氨蝶呤胎囊注射联合B超监测下清宫术治疗。对比两组患者的临床效果、月经恢复时间、包块消失时间、血人绒毛膜促性腺激素（HCG）转阴时间、阴道出血时间、住院时间及治疗前、治疗后2个月生活质量评分（SF-36）。结果 试验组治疗后总有效率（88.64%）高于对照组（67.44%）,差异有统计学意义（P<0.05）;与对照组相比,试验组包块消失时间、血HCG转阴时间、阴道出血时间、住院时间均较短,差异有统计学意义（P<0.05）;两组患者治疗后2个月SF-36评分均提高,且试验组提高水平高于对照组,差异有统计学意义（P<0.05）。结论 剖宫产瘢痕妊娠患者予以甲氨蝶呤胎囊注射联合B超监测下清宫术治疗可明显改善临床效果,缩短患者恢复时间,改善患者生活质量。     

Comparing methods for clinical investigator site inspection selection: a comparison of site selection methods of investigators in clinical trials

ABSTRACT

Background During the past two decades, the number and complexity of clinical trials have risen dramatically increasing the difficulty of choosing sites for inspection. FDA’s resources are limited and so sites should be chosen with care.

Purpose To determine if data mining techniques and/or unsupervised statistical monitoring can assist with the process of identifying potential clinical sites for inspection.

Methods Five summary-level clinical site datasets from four new drug applications (NDA) and one biologics license application (BLA), where the FDA had performed or had planned site inspections, were used. The number of sites inspected and the results of the inspections were blinded to the researchers. Five supervised learning models from the previous two years (2016–2017) of an on-going research project were used to predict site inspections results, i.e., No Action Indicated (NAI), Voluntary Action Indicated (VAI), or Official Action Indicated (OAI). Statistical Monitoring Applied to Research Trials (SMART^TM) software for unsupervised statistical monitoring software developed by CluePoints (Mont-Saint-Guibert, Belgium) was utilized to identify atypical centers (via a p-value approach) within a study.Finally, Clinical Investigator Site Selection Tool (CISST), developed by the Center for Drug Evaluation and Research (CDER), was used to calculate the total risk of each site thereby providing a framework for site selection. The agreement between the predictions of these methods was compared. The overall accuracy and sensitivity of the methods were graphically compared.

Results Spearman’s rank order correlation was used to examine the agreement between the SMART^TM analysis (CluePoints’ software) and the CISST analysis. The average aggregated correlation between the p-values (SMART^TM) and total risk scores (CISST) for all five studies was 0.21, and range from ?0.41 to 0.50. The Random Forest models for 2016 and 2017 showed the highest aggregated mean agreement (65.1%) amongst outcomes (NAI, VAI, OAI) for the three available studies. While there does not appear to be a single most accurate approach, the performance of methods under certain circumstances is discussed later in this paper.

Limitations Classifier models based on data mining techniques require historical data (i.e., training data) to develop the model. There is a possibility that sites in the five-summary level datasets were included in the training datasets for the models from the previous year’s research which could result in spurious confirmation of predictive ability. Additionally, the CISST was utilized in three of the five site selection processes, possibly biasing the data.

Conclusion The agreement between methods was lower than expected and no single method emerged as the most accurate.     

Regulated LC-MS/MS bioanalysis technology for therapeutic antibodies and Fc-fusion proteins using structure-indicated approach

In recent studies, the development of bioanalysis technologies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has attracted attention. Our developed nano-surface and molecular-orientation limited (nSMOL) proteolysis enables Fab-specific proteolysis and is optimal for LC-MS/MS analysis of antibody drugs and Fc-fusion proteins in biological samples. In this nSMOL method, antibodies and Fc-fusion proteins are held in pores of the particle and the subsequent proteolysis is carried out with protease-immobilized nanoparticles. The Fab of antibodies or fused region of Fc-fusion protein can be held to orient toward the reaction solution. The access of the immobilized protease is limited to a part in the structure of protein substrate on the particle surface. Thus, nSMOL proteolysis reacts selectively at the Fab complementarity-determining region of antibodies or N-terminal specific domain of Fc-fusion proteins and can be applied to both types of drugs. We have already evaluated drug concentrations in biological samples pretreated with nSMOL proteolysis using LC-MS/MS for more than twenty drugs, of which ten drugs have been fully validated and published. In this review, we discuss the development and application of LC-MS/MS bioanalysis, which enables the bioanalysis of therapeutic antibodies and Fc-fusion proteins by focusing on a structure-based approach.     

Therapeutic drug monitoring of monoclonal antibodies: Applicability based on their pharmacokinetic properties

Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fc-receptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs. On the other hand, flat exposure-efficacy relationships of anti-PD-1 antibodies nivolmab and pembrolizumab mean ensuring absolute maximum efficacy in each patient by the approved dose regardless of their large interpatient variability in pharmacokinetics. Administration of mAbs can induce production of anti-drug antibodies (ADAs), which impact on their pharmacokinetics and pharmacodynamics. In therapeutic drug monitoring (TDM) of mAbs, when total (free, soluble target bound and ADAs bound) mAbs concentration is measured, ADAs content (concentration/titer) should be also monitored because mAbs exists in inactive complex with ADAs. Along with determination of appropriated therapeutic windows taking into account ADAs content, treatment algorithms for TDM-guided clinical decision-making must be developed and prospectively shown to be superior to traditional clinical care for each mAb in each indication.     

临床药师参与1例血液透析伴尿路感染患者万古霉素个体化用药方案制定

摘 要对临床药师参与的1例血液透析患者伴复杂性尿路感染使用万古霉素的病例进行讨论和分析,分享高通量血透伴复杂性尿路感染使用万古霉素进行抗感染治疗的经验。临床药师结合复杂性尿路感染常见致病菌、耐药情况、万古霉素在高通量血液透析中PK/PD参数、血清药物浓度监测、制定个体化的万古霉素给药方案。通过对药物治疗方案的调整,患者万古霉素血清药物浓度达到治疗窗范围,感染得到了控制,治疗过程中未出现万古霉素相关的肾毒性等不良反应。证实了临床药师在肾衰竭血液透析特殊患者的药物治疗中,能协助医生发挥优化治疗方案的作用,可以改善临床药物治疗效果,促进临床合理用药。     

康艾注射液上市后医院集中监测

摘 要 目的：对康艾注射液上市后临床应用情况进行评价,为规范和指导临床合理用药提供依据。方法：采用医院集中监测的方法,以本院2016年11月～2017年3月入院并使用康艾注射液的住院患者为研究对象,记录患者基本情况、用药情况和药品不良反应发生情况,并评价用药合理性。 结果：共观察病例1 000例,其中超适应证用药占2.5%,用药剂量不足占2.1%,超疗程用药占0.8%,溶媒剂量不足占0.5%。1例患者发生药品不良反应,发生率为0.1%。结论：康艾注射液临床应用欠规范,提示临床用药应严格按照说明书规定适应证、疗程和用法用量,并密切监护患者有无不良反应发生等。     

我院重点监控药品监管前后合理用药指标变化

摘 要 目的：加强监管医院重点监控的药品,在新医改形势下降低药品费用,提升临床用药管理水平。方法：通过制定医院重点监控药品目录、药师监控全方位覆盖、结合医保每日点评、三级培训、厂家约谈、停药公示、目录优化调整、信息化管控、绩效考核等措施建立重点监控药品合理使用长效管理体系,并对我院建立重点监控药品监管前（2017年5月）与监管后（2018年5月）药占比、重点监控药品占比、基本药物使用比例、重点监控药品不合理用药比例、销售金额前10位药品排序进行统计分析。结果：与监管前比较,监管后我院药占比从45.52%降至32.46%,降幅为28.69%;重点监控药品占比的降幅为37.03%,不合理用药比例的降幅为41.35%;抗菌药物使用强度的降幅为11.6%;基本药物使用比例的增幅为6.64%;人均住院用药品种数量从8.17种降至6.96种,降幅为14.81%;销售金额前10位药品中出现了临床治疗指南推荐的治疗用药。结论：医院应结合院内用药特点、当地重点监控药品监管办法及医保政策从停药、针对性的医师处方权限制、信息化监管、重点监控药品目录调整、合理用药点评及培训等环节进行相应监管,从而促进重点监控药品的监控管理,降低药占比,提高合理用药水平。