以患者为中心的药物研发策略

介绍美国食品及药物管理局（FDA）以患者为中心的药物开发思路,展示了不同疾病、治疗收益、使用环境分别对应的临床结局评估（COA）工具,整理出5个已获批患者报告结局（PRO）工具的相关信息,并归纳了2010—2015年FDA获批新药中,应用PRO评估工具支持说明书相关声明的药品信息。旨在为业界选择适合的COA类型（PRO、ClinRO、ObsRO或PerfO评估工具）应用于药物研发提供借鉴,并建议将COA工具用于儿科、罕见病、认知障碍相关疾病以及中药的临床疗效评估;同时也为将患者的观点纳入药品监管流程提供参考。     

Hair analysis of antidepressants and antipsychotics—Overview of quantitative data

Antidepressant and antipsychotic drugs are regularly encountered in different aspects of forensic toxicology, and some cases require the examination of hair samples. In this study, common antidepressant and antipsychotic drugs regarding hair concentrations over the past decades were reviewed. Although numerous publications around method validations, case reports, or controlled dose studies were found, apparently there is a lack of comprehensive data for many substances. Information on the hair length and dosage across the publications varied largely, and case numbers were generally low except for several retrospective controlled dose studies. Many substances were described only in method validations or case reports, and data were obtained from small case numbers. On the contrary, clozapine, haloperidol, amitriptyline, nortriptyline, risperidone and its metabolite, methylphenidate, citalopram, chlorpromazine, chlorprothixene, and quetiapine had a well‐founded database as these substances were investigated in controlled dose studies with higher case numbers. Given the advancements made in analytical techniques over the past years, gas chromatography–mass spectrometry and liquid chromatography with tandem mass spectrometry techniques were the methods of choice and allowed the detection of chemical compounds at low concentrations. The controversy around a potential use of hair analysis to estimate the dosage remains as dose‐concentration studies provided divergent results. A harmonization on the investigated hair length as well as on the extraction protocol would be of favor to achieve better comparability. Although hair analysis research focused mainly on drug abuse, availability of more data on antidepressants and antipsychotics would help to gain better knowledge and assist other forensic investigators.     

Segmental analysis of antidepressant and antipsychotic drugs in the hair of schizophrenic patients

Hair analysis is useful for documenting long‐term exposure to drugs. The potential of hair analysis for therapeutic drug monitoring within the forensic field has been studied, but reference values for some antidepressants and antipsychotics in the hair of individuals undergoing chronic therapy are still lacking. In the present study, a method was developed and validated for the determination of 23 analytes, including antidepressants, antipsychotics, and related metabolites, in human hair by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Hair samples (10 mg) were extracted with a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3) utilizing cryogenic grinding. The present method demonstrated sufficient selectivity, robustness, and accuracy. Sixteen analytes in hair were reported in 46 psychiatric patients receiving fixed drug dosages. To the best of our knowledge, the hair concentrations of perphenazine and norolanzapine, as well as the concentrations of amisulpride, aripiprazole and its metabolite dehydroaripiprazole, olanzapine, and sulpiride, in hair from individuals receiving fixed dosages is reported for the first time. A significant relationship between the administered dose and the concentration in the proximal hair segment was found only for clozapine, norclozapine, and chlorpromazine. The results confirmed that the idea of using hair concentrations to monitor a daily dose is inapplicable.     

Design,microwave‐assisted synthesis,biological evaluation and molecular modeling studies of 4‐phenylthiazoles as potent fatty acid amide hydrolase inhibitors

Endocannabinoids, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti‐inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2‐naphthyl‐ and 4‐phenylthiazole scaffolds were identified, but up to the present time, very little structure–activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.     

疫苗生产中基于风险评估的清洗剂变更

目的 在白喉-破伤风-无细胞百日咳疫苗生产车间玻璃瓶清洗剂的变更中,引入质量风险管理,对新清洗剂进行风险分析与评估,以确保更换清洗剂对产品质量无影响。方法 运用风险评估工具对新清洗剂进行相应风险评估,根据风险级别制定风险控制措施,对新清洗剂进行验证,确认其清洗效果以及对产品的影响。结果 清洗后玻璃瓶淋洗水中细菌内毒素含量≤0.25内毒素单位/ml、总好氧微生物计数≤100菌落形成单位/ml、总霉菌酵母菌计数≤10菌落形成单位/ml、总有机碳≤1.5 μg/cm2（淋洗水和擦拭取样）、电导率≤1.3 µS/cm,结果均符合要求。结论 在变更控制中运用质量风险管理,指导变更控制措施的制定和变更内容的实施,保证了新清洗剂的风险可接受且产品质量不受变更影响。     

临床药师参与门诊疼痛综合评定的工作实践

目的:探讨中山大学肿瘤防治中心临床药师参与门诊开展疼痛综合评定的工作模式及其效果。方法:采用回顾性病例对照研究方法,将2017年10月至2018年3月临床药师未参与疼痛综合评定时在疼痛门诊就诊的74例患者作为对照组(由医师进行癌性疼痛评估),2018年4月至2018年9月临床药师参与疼痛综合评定后在疼痛联合门诊就诊的78例患者作为疼痛综合评定组(由临床药师参与疼痛综合评定),比较两组患者入组前、入组2周后的疼痛控制、疼痛对生活质量的影响及用药依从性的变化。结果:入组2周后,两组患者的各项指标水平均较入组前明显改善,且疼痛综合评定组患者的疼痛控制、疼痛对生活质量的影响及用药依从性的变化均明显优于对照组,差异均有统计学意义(P<0.05)。结论:建立肿瘤专科医院临床药师参与疼痛联合门诊疼痛综合评定的工作模式,有助于提高患者的用药依从性,可明显改善患者的疼痛控制、疼痛对生活的影响。     

UPLC-MS/MS法测定人血浆中卡马西平浓度

目的:建立UPLC-MS/MS法测定人血浆中卡马西平浓度并进行方法验证,应用于室间质评的样品测定。方法:采用UPLC-MS/MS法,以卡马西平-d8为内标,XSelect CSH C18柱(2.1 mm×75 mm,2.5μm)为分析柱,流动相A为含0.05%甲酸的水溶液,流动相B为含0.05%甲酸的乙腈溶液,流速为0.3 mL·min^-1,梯度洗脱;采用电喷雾离子源,以多反应监测(MRM)正离子模式进行检测,用于定量分析的离子对为m/z 237.1→194.1(卡马西平)、m/z 245.0→202.1(卡马西平-d8)。结果:卡马西平在5~1000 ng·mL^-1范围内线性关系良好(r≥0.9993),批内批间精密度和准确度、回收率和基质效应以及稳定性均符合生物样品测定要求。应用该方法测定的室间质评样品结果全部通过。结论:该方法准确、灵敏、选择性好、重现性高,适用于血浆中卡马西平浓度测定及室间质评。     

Is Pain Assessment of Community-Dwelling Persons With Advanced Dementia by Family and Paid Care Workers Feasible?

ContextThe experience of pain is aggravated among older persons with advanced dementia (OPAD). It is often undetected and therefore untreated because of their limited capacity to identify and report their symptoms. Therefore, it is crucial to improve the pain identification skills of those who know and live with them.ObjectivesTo compare the identification of pain among OPAD between family members and paid care workers and to compare the detection of pain through the use of two common assessment tools.MethodsThis study is a cross-sectional comparison conducted between 82 dyads of informants: the family member of OPAD and the paid care worker, a total of 164 individuals.MeasurementsThe study used two previously validated pain assessment tools for persons suffering from dementia: the Pain Assessment in Noncommunicative Elderly persons tool (PAINE) and Pain Assessment in Advanced Dementia tool (PAINAD), and a general impression question.ResultsBoth family members and paid care workers were able to successfully use both tools. The correlation between family members' ratings and paid care workers' ratings was statistically significant for all the assessments. The correlations between raters were higher when family members lived with the OPAD. The correlations between PAINE and PAINAD scores were moderate and significant, both among family members and paid care workers.ConclusionThis study shows that it is feasible to improve the assessment and identification of pain among OPAD, through the use of validated tools by family members and paid care workers, suggesting the potential to improve quality of care and quality of life of OPAD.