生物检定的现状和发展

生物检定在药品质量的常规检验以及对一些未知结构化合物活性的测定中占有重要的地位。我国生测工作者除坚持现有生测品种的检定工作外,还应适应发展需要,拓宽工作面,与现代先进技术配合,把好药品质量关。     

Developing an analytical toxicology service: principles and guidance

Many acutely poisoned patients are treated with no laboratory help other than general clinical chemistry and haematology. Emergency toxicological analyses (24-hour availability) that could influence immediate patient management such as iron, lithium and paracetamol (acetaminophen), are relatively few in number and are remarkably similar worldwide. These assays should be provided at hospitals with large accident and emergency departments. More complex, less frequently needed clinical toxicological assays that can often be offered on a less urgent basis are usually provided from regional or national centres because of the need to make best use of resources. Recommendations as to the assays that should be provided locally and at regional centres are available for the UK and US, and are generally applicable. Regional centres normally diversify into specialised therapeutic drug monitoring, urine screening for drugs of abuse, metals analysis and sometimes forensic work in order to widen the repertoire of tests available and to increase funding. Whatever the type and quantity of work undertaken and the instrumentation used, guidelines are now available delineating staff training, method validation, assay operation, quality control/quality assurance, and indeed virtually all other aspects of laboratory operation. These considerations notwithstanding, clinical interpretation of analytical results remains a difficult area and is the responsibility of the reporting laboratory, at least in the first instance.     

Developing an Analytical Toxicology Service

Many acutely poisoned patients are treated with no laboratory help other than general clinical chemistry and haematology. Emergency toxicological analyses (24-hour availability) that could influence immediate patient management such as iron, lithium and paracetamol (acetaminophen), are relatively few in number and are remarkably similar worldwide. These assays should be provided at hospitals with large accident and emergency departments. More complex, less frequently needed clinical toxicological assays that can often be offered on a less urgent basis are usually provided from regional or national centres because of the need to make best use of resources. Recommendations as to the assays that should be provided locally and at regional centres are available for the UK and US, and are generally applicable. Regional centres normally diversify into specialised therapeutic drug monitoring, urine screening for drugs of abuse, metals analysis and sometimes forensic work in order to widen the repertoire of tests available and to increase funding. Whatever the type and quantity of work undertaken and the instrumentation used, guidelines are now available delineating staff training, method validation, assay operation, quality control/quality assurance, and indeed virtually all other aspects of laboratory operation. These considerations notwithstanding, clinical interpretation of analytical results remains a difficult area and is the responsibility of the reporting laboratory, at least in the first instance.     

全国药检系统实验动物工作情况及建议

目的 为提升药检系统实验动物工作对食品、药品、医疗器械检验检测工作的技术支撑能力和服务保障水平提供依据和参考.方法 采用调查问卷的方式对调查数据进行汇总统计,全面了解我国药检系统实验动物的生产、使用和管理水平,分析存在的主要问题,提出建设性意见.结果与结论 建议加强机构管理和人员队伍的建设,提高实验动物质量,丰富实验动物资源,推动实验动物工作的可持续发展.     

食品药品监管系统微生物实验室质量控制探讨

目的随着检测范围的扩大和检测指标的增加,食品药品监管系统微生物实验室质量控制体系面临新的挑战。本文讨论微生物实验室质量控制关键问题,为食品药品监管系统微生物实验室管理提供参考。方法从实验室设施建设、试验人员操作培训、实验室质量管理3个方面,对微生物实验室质量控制关键点进行总结和分析。结果与结论加强设施建设,满足规范要求,合理整合资源,加强生物安全管理;注重人员操作培训及技术延伸软件建设;加强实验室质控关键点的管理,重视实验室比对和能力验证工作,是微生物实验室在新形势下提高综合质量控制水平的主要方面。     

食品药品能力验证可疑或不满意结果风险点分析与对策

目的：能力验证是反映实验室质量管理体系有效性的重要手段,对隐藏的风险有预测和预警作用,针对常见的可疑或不满意结果分析原因和案例,汇总自查与整改情况,归纳造成结果偏离的常见原因和关键控制点,据此分析实验室存在的风险点和给出对策。方法：通过举例分析,查找实际检验工作中有代表性的重点、难点,举一反三,总结出经验教训。结果与结论：个别结果偏离虽有一定的偶然性,但也可反映日常检测活动的风险点,高度重视自查与整改过程,实事求是分析失误原因与提出对策,不片面,不避重就轻,从而在检测活动中避免发生相同的错误,这是检验实验室质量保证的一项有益、重要的措施,充分实现能力验证对质量控制和检测水平持续提升的效果。     

自建色谱法血药浓度监测靶值建立及与不同方法测定水平的比较——以硫唑嘌呤代谢物和卡马西平为例

目的：探索自建色谱法血药浓度监测靶值的建立；对比色谱法和免疫法在血药浓度测定的水平差异。方法：选择安徽医科大学第一附属医院硫唑嘌呤代谢物和卡马西平血药浓度监测分别作为实验室自建色谱法和不同测定方法的项目代表。回顾性分析硫唑嘌呤代谢物部分质控数据，以即刻质控法初步建立室内靶值，Westgard多规则质控对该项目开展常规质控；43例卡马西平样本分别由实验室HPLC和全自动生化分析仪以及第三方医学实验室，通过相关和回归分析评价检验方法一致性。结果：硫唑嘌呤代谢物项目在第16次质控监测提示告警，第17次失控记录也证实其存在异常离群。常规检测过程中累积失控2次即2_2s及1_3s记录各1次。三水平质控品累积变异系数分别为8.85%、7.46%和4.73%。3组卡马西平血药浓度测定数据均为非正态分布，其中实验室免疫法测定质量浓度结果最高（中位数为6.00 μg·mL^-1），第三方实验室测定结果次之（中位数为5.50 μg·mL^-1），而实验室色谱法测定结果最小（中位数为3.80 μg·mL^-1）。第三方实验室与实验室免疫法、第三方实验室与实验室色谱法以及实验室色谱法与免疫法其3组方法比较的秩相关系数分别为0.984、0.975和0.956，Passing-Bablok回归方程分别为：y=0.298+0.817x，y=-0.246+1.539x，y=-1.009+1.947x。结果表明，以上测定方法的一致性较好。结论：即刻质控法可用于自建色谱法血药浓度监测的简易室内质控程序。色谱法和免疫法在卡马西平血药浓度测定中存在基线水平差异。     

地市级药检所执行《实验室资质认定评审准则》应重视的几个问题

目的探讨地市级药检所执行《实验室资质认定评审准则》应重视的几个问题。方法分析地市级药检所实验室资质认定过程中,在人员培训、仪器设备、记录、文件控制、质量监督五个方面如何加强实验室管理体系建设。结果与结论通过实施实验室资质认定,基层药检所要强化软件管理。     

Biomarkers,validation and pharmacokinetic-pharmacodynamic modelling

Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process. Data from genomic and proteomics differentiating healthy versus disease states lead to biomarker discovery and identification. Multiple genes control complex diseases via hosts of gene products in biometabolic pathways and cell/organ signal transduction. Pilot exploratory studies should be conducted to identify pivotal biomarkers to be used for predictive clinical assessment of disease progression and the effect of drug intervention. Most biomarkers are endogenous macromolecules, which could be measured in biological fluids. Many exist in heterogeneous forms with varying activity and immunoreactivity, posting challenges for bioanalysis. Reliable and selective assays could be validated under a GLP-like environment for quantitative methods. While the need for consistent reference standards and quality control monitoring during sample analysis for biomarker assays are similar to that of drug molecules, many biomarkers have special requirements for sample collection that demand a well coordinated team management. Bioanalytical methods should be validated to meet study objectives at various drug development stages, and possess adequate performance to quantify biochemical responses specific to the target disease progression and drug intervention. Protocol design to produce sufficient data for PK/PD modelling would be more complex than that of PK. Knowledge of mechanism from discovery and preclinical studies are helpful for planning clinical study designs in cascade, sequential, crossover or replicate mode. The appropriate combination of biomarker identification and selection, bioanalytical methods development and validation for drugs and biomarkers, and mechanism-based PK/PD models for fitting data and predicting future clinical endpoints/outcomes provide powerful insights and guidance for effective and efficient rational drug development, toward safe and efficacious medicine for individual patients.     

全国药检系统实验室间比对工作的分析和思考

目的为药检系统实验室质量管理提供依据。方法通过对2009年至2011年全国药检系统实验室比对工作的分析和研究,了解药检系统实验室检验技术和质量管理体系的现状。结果大部分省级以上药品检验机构的检验技术和实验室质量管理体系满足要求。结论药检系统实验室间比对工作是保障检验质量的重要手段,应建立长效机制。     

Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know

The direct acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have favorable pharmacokinetic and pharmacodynamic properties and equal or superior efficacy and an improved safety profile compared with warfarin. Noted shortcomings with DOACs are shorter half‐lives requiring stricter adherence, lack of standardized laboratory monitoring, lack of anticoagulation reversal agents, and loss of routine coagulation monitoring leading to fewer patient–clinician interactions. This review addresses many of these limitations including monitoring of DOACs for efficacy and toxicity, an assessment of selected qualitative and quantitative tests, and development of monitoring strategies for special populations. Coagulation monitoring is generally recommended only in overdose situations, but once standardized assays are readily available, they could be helpful to ensure efficacy, assess bleeding, and aid in drug selection in a number of other patient scenarios. Coagulation tests that may provide qualitative assessment include activated partial thromboplastin time, prothrombin time, and thrombin time. Methods with potential utility for quantitative assessment of DOACs include plasma drug concentrations, ecarin clotting time, dilute thrombin time, and anti–factor Xa concentrations. Noncoagulation laboratory monitoring should include serum creatinine, liver function tests, and complete blood counts. Clinical monitoring of the DOAC‐treated patient should include routine assessment of adherence, bleeding risks, and drug interactions. Frequency of monitoring should be 1–3 months after initiation and then at least every 6 months, with more frequent follow‐up (i.e., 3 months) based on patient specific characteristics such as age, renal impairment, hepatic impairment, and concomitant drug therapy. The authors provide a practical tool to assist in DOAC monitoring and recommend that pharmacists collaborate with physicians in selecting appropriate patients and tailoring patient‐specific monitoring plans.     

Audits of radiopharmaceutical formulations.

A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team.     

临床实验室检验结果比对与结果互认分级的临床研究

目的：探讨临床实验室检验结果比对与结果互认分级。方法在实验室质量控制资料基础上,对几家二级以上医院常规检查项目进行质量检验、现场调查,对医院间检验结果互认进行分级和可行性分析。结果同等级医院间可以开展检验结果互认,不同等级医院间不宜开展检验结果互认,确定检验结果互认的专业项目应以由易到难的原则,同时做好检验质量的监督管理。结论做好现场调查和现场考核,加强实验室检验质量的管理和监督,确保实验室检验结果互认的顺利完成。     

医院药检室工作现状及发展探讨

目的:加强医院药检室的职能作用。方法:综合分析医院药检室的现状和开展的主要工作。结果:药检室的职能工作已从对自制药品的质量控制逐步扩大到对全院的药品质量监督,并逐步深入到为临床解决实际工作中遇到的问题。结论:应进一步加强药检室的作用,实现其工作重心从"以药品为中心"到"以病人为中心"的转变,提高医院医疗服务质量,促进合理用药。     

Best practice in therapeutic drug monitoring

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regime and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring . This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process—the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management—are discussed.     

浅谈医院药物临床试验质量控制体系的建设

目的 介绍本院执行《药物临床试验质量管理规范》（GCP）的工作经验,探讨医院药物临床试验质量控制体系的建设.方法 总结了药物临床试验在知情同意、试验的实施及实验室检查方面存在的问题.介绍了本院以GCP为指导原则,完善制度和标准操作规程、建立“三级质控”工作模式、强化GCP培训、加强机构内部的沟通协调、着力提升新药临床试验质量的具体做法和经验.结果与结论 新药必须在人体进行临床试验才能最终确定药物的有效性和安全性.医院药物临床试验机构建立完善的临床试验质量控制体系,有利于为公众筛选安全、有效的药物,推动医药卫生事业的进步与发展.     

Drugs and children: methods for therapeutic monitoring.

In this era of polypharmacy, the incidence of adverse reactions due to drug therapy has increased alarmingly since the precise effects on the metabolism of a drug given in combination with other drugs can never be predicted with certainty. Inadequate therapy due to insufficient medication or to factors which diminish absorption or enhance metabolism may be equally undesirable. The consequences to patients in terms of increased morbidity and financial cost of prolonged hospitalization may be considerable. For pediatric patients, particularly in the newborn period, these hazards may be much more dangerous. There is a need for more investigation into the validity of procedures in current use for the determination of drug levels in biologic fluids and into the interpretation of the values they produce. In addition clinical chemists and clinical pharmacologists are faced with the challenge of defining those drugs for which blood level information would be advantageous and developing rapid, sensitive, and accurate assays which can be performed by the routine clinical laboratory. The day may be not too far away when a major proportion of the workload of the clinical laboratory consists of assays primarily designed as an aid to therapy rather than diagnosis.     

Laboratory support of drug abuse control programs: an overview.

Labeling an individual a drug abuser has serious sociologic and legal implications that only laboratory testing can effectively allay. A proper specimen (both qualitatively and quantitatively) must be obtained for analysis. Positive identification of specimen with subject is of paramount importance. The problems of specimen substitution--other people's urine, tap water, apple juice--directly impinge here, as does the possibility of drug degradation by heat, light, and microbial attack and of drug adsorption by the container and urinary sediment. Confirmation of postives indicated by screening tests (thin layer chromatography and immunoassays) by gas chromatography and/or ultraviolet spectrophotometry is, in most situations, mandatory. An effective quality control program is an absolute requirement. Even under ideal circumstances, laboratory results can sometimes wrongly indicate the abuse of drugs; and conversely, drug abuse can take place without detection by the laboratory. As in any clinical situation, laboratory tests are only a part (albeit an important one) of the entire evaluation of the individual involved.     

Oxidative stress assays for disease risk stratification

Despite the fact that oxidative stress is a significant aetiological factor in several degenerative diseases, its measurement is rarely a part of "routine analyses" performed in hospital clinical chemistry laboratories. This situation is likely to change, as interest in this topic is increasing rapidly. Here we review the pertinent literature, with an assessment of assays for oxidative stress, and categorize them under: (i) assays for monitoring lipid peroxidation, (ii) assays for measuring oxidized amino acids, (iii) assays for measuring oxidized nucleic acids, (iv) assays based on physicochemical and immunological properties of oxidized low-density lipoprotein, and (v) assays for measuring the antioxidant capacity of body fluids and tissues. Our overview should be of help when choosing appropriate laboratory assays for oxidative stress and for routine disease risk stratification.     

Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation

For patients with epilepsy, effective seizure control is the most important determinant of good quality of life. To achieve this, antiepileptic drug (AED) dosages should be individualised to maximise therapeutic benefit and to avoid most--if not all--adverse effects. Several studies suggest that, in routine clinical practice, dosage individualisation is often suboptimal. This may lead to patients receiving unnecessarily large dosages. Conversely, it may lead to patients switching to an alternative therapy (when clinical response is deemed insufficient), without exploration of the full dosage range. Indeed, dosage optimisation--which should involve consideration of the treatment setting and individual patient characteristics--can be a complicated process requiring skill and patience. In general neurological practice, most AEDs should be started at a low dosage and gradually titrated upwards. Starting dosages are similar in most types of epilepsy; however, if a rapid onset of therapeutic action is required, phenytoin, phenobarbital (phenobarbitone), levetiracetam and gabapentin are probably the best tolerated AEDs for starting at full dosage. The initial target maintenance dosage of an AED should be based on the dose-response profile of the drug, and on specific patient characteristics. Usually, the lowest effective daily dose expected to provide seizure control should be used, although various factors (e.g. stage and severity of epilepsy, pharmacokinetic and pharmacodynamic considerations, attitude of the patient) will markedly influence dosage selection. If seizures are not controlled on the initial target dose, the dosage should be increased gradually until complete seizure control is achieved or intolerable adverse effects occur. In most patients who fail to respond to the initially prescribed drug, switching to another AED (monotherapy) is the best option. Combination therapy may be appropriate for patients unresponsive to 2 or more sequential monotherapies. Therapeutic drug monitoring (measurement of serum drug concentrations) is useful in various settings, such as when drug interactions are expected, toxicity is suspected, or when AEDs with nonlinear pharmacokinetics (e.g. phenytoin, carbamazepine) are used. No indications currently exist for routine therapeutic drug monitoring of the newer AEDs. In summary, dosage regimens of AEDs should be assessed regularly, and adjusted if necessary, so that patients can derive optimal therapeutic benefit. For patients considered 'difficult to treat' (i.e. those in whom seizures remain incompletely controlled after several attempts at treatment), referral to a specialist is recommended.