Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

中药酊剂临床外用技术规范(草案)

基于对中药酊剂外用技术的数据挖掘,结合临床实际应用研究,经外治学会专家多次论证,形成中药酊剂临床外用技术规范(草案),包括临床适用范围、操作步骤以及外用酊剂的方法、剂量、频率、时间、注意事项、不良反应及护理要点。以期规范中药外用酊剂的临床应用,提高其疗效并减少不良反应。     

蒲地蓝消炎口服液联合氢定乳膏治疗PICC局部湿疹临床观察

目的观察蒲地蓝消炎口服液联合应用氢定乳膏治疗PICC局部湿疹的疗效。方法采用病例对照研究的方法,选择PICC门诊2014年1月-2018年12月PICC局部湿疹患者80例,随机分为实验组39例和对照组41例,观察组用蒲地蓝消炎口服液联合氢定乳膏加局部敷料开窗法进行护理。对照组用氢定乳膏加局部敷料开窗法,比较2组的临床疗效。结果观察组39例,总有效34例(87.18%);对照组41例,总有效23例(56.10%)。2组比较差异具有统计学意义(P<0.01)。结论蒲地蓝消炎口服液联合氢定乳膏治疗PICC局部湿疹的效果优于对照组。     

经典名方地黄饮子的古代文献考究

经典名方地黄饮子现代临床应用广泛,治疗多科疾病,尤其是内科病中的神经系统疾病较多,临床疗效确切,但目前尚未转化成中成药制剂。故笔者采用文献计量学的方法,搜集记载地黄饮子的中医古籍文献,筛选、整理出有效数据254条,涉及中医古籍144部,系统梳理和分析研究了地黄饮子的历史发展源流、主治病证、制方原理、用药剂量、制剂方法、煎服方法等,以期为经典名方的研发和临床应用提供古代文献证据支持。研究发现,地黄饮子出自金代医家刘河间所著《宣明论方》,由熟地黄、巴戟天、山茱萸、肉苁蓉、石斛、附子、五味子、官桂、白茯苓、麦门冬、藏菖蒲、远志12味药物组成,主治喑痱。后世记载的地黄饮子多遵从《宣明论方》中的方剂组成和主治,且临床应用有所扩展,在有主治病证记载的199条文献中,喑痱最多,约占总病证的一半;其次为中风,约占五分之二;亦用于暴喑、痿证、眩晕、遗尿等病证。地黄饮子治疗病证范围较广,但病机总属"肾中水火俱亏"。其制方独特,上下并治,标本兼顾,尤以治下治本为主。在有药物用量记载的56条文献中,约有三分之一继承了《宣明论方》的记载:"等分,上为末,每服3钱。"药物用量总体偏轻。制剂多为汤剂、煮散,在煎服方法上主张"浊药轻投""数滚即服""不计时候"。     

How is safety of dermatology drugs assessed: trials,registries, and spontaneous reporting

ABSTRACT

Introduction: Skin conditions are common and highly varied in their etiology; therefore, a diverse array of therapeutics are utilized. Drug safety studies in dermatology can be challenging as there are over 3000 diagnoses to consider. As a result, dermatologists rely on data from multiple sources including clinical trials and real-world evidence.

Areas covered: In this review, we cover the main sources of safety data available, their strengths and weaknesses and how dermatologists should utilize such data. We use real-world examples of the different types of adverse events reported and how they are best captured by either randomized controlled trials or post-marketing pharmacovigilance methods. With multiple new therapies in dermatology, such as dupilumab for atopic dermatitis and janus-kinase inhibitors for alopecia areata the specialty is awash with evolving high-level evidence for their use. It is important to understand the optimal way to assess safety from trials but also appreciate the need for ongoing capture of safety data in clinical practice.

Expert opinion: In dermatology, there is a plethora of conditions to treat and clinical trials, post-marketing surveillance, such as drug registries and spontaneous reporting, all enable dermatologists to gain a more comprehensive understanding of the safety profiles of drugs being used.     

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty‐seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1‐7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8‐2.7) for prophylaxis and 1.76 mg/L (IQR 1.3‐2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.     

左旋肉碱修饰的壳聚糖-硬脂酸协载槲皮素口服紫杉醇纳米胶束的制备、表征及在体肠循环研究

目的 制备左旋肉碱修饰的壳聚糖-硬脂酸（LC-SA/CS-SA）纳米胶束，包载紫杉醇（PTX）且协载槲皮素，考察胶束特性，并以大鼠在体肠循环评估给药系统对PTX口服吸收的促进作用。方法 将硬脂酸（SA）通过酰胺化反应接枝于壳聚糖（CS），形成共聚物CS-SA；采用核磁共振H谱、红外光谱鉴定产物结构；以PTX为主药，槲皮素为辅药，采用激光粒径分析、Zeta电位分析和HPLC分析分别考察了胶束的粒径、Zeta电位、载药量、包封率；透射电子显微镜观察胶束形貌；芘荧光探针法测定LC-SA/CS-SA胶束的临界胶束浓度（critical micelle concentration，CMC）；透析袋法考察胶束的体外释放行为；大鼠在体肠吸收实验评估载药胶束的促吸收作用。结果 红外与核磁结果表明SA通过酰胺键接枝于CS；协载槲皮素的LC-SA/CS-SA载PTX胶束呈类球形，粒径为（148.3±1.7）nm，多分散系数（PDI）为0.16±0.07，Zeta电位为（24.600±0.167）mV，CMC为14.31 μg/mL；体外释放结果表明，与市售紫杉醇注射剂相比，协载槲皮素的LC-SA/CS-SA载PTX胶束、LC-SA/CS-SA载PTX胶束具有明显缓释效应；大鼠在体肠吸收实验表明，协载槲皮素的LC-SA/CS-SA胶束对载药PTX的胃肠吸收具有显著促进作用。结论 构建的协载槲皮素的LC-SA/CS-SA载PTX胶束性能优良，促进了PTX的大鼠肠吸收，具有增强药物口服吸收潜力。     

Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.     

美国新药技术成熟度评价研究

目的研究提出适合我国新药研发和药品安全管理的技术成熟度评价机制。方法借鉴美国新药研发技术成熟度等级(biomedical technology readiness level,BTRL)评价标准与方法,结合我国新药研发、监管和产业化特点,提出我国成熟度评价等级和指标,并在重大新药创制科技重大专项研发管理中开展探索分析。结果与结论探索建立我国化学药和生物制品技术成熟度评价等级标准,将为我国新药研发科研项目和保障药品安全提供管理与评估工具,为其他行业领域提供参考借鉴。     

全国名中医丁书文益气活血解毒法治疗心房颤动的处方用药规律挖掘＊

目的 丁书文教授创新性地提出了心系疾病热毒学说，运用益气活血解毒法治疗房颤疗效显著。本研究以丁教授多年的处方数据为基础，探讨丁教授益气活血解毒法治疗房颤的用药规律。方法 收集来自山东中医药大学附属医院门诊系统的丁书文教授处方数据，筛选出治疗房颤的372个处方，采用关联规则、点式互信息、复杂网络等数据挖掘方法对丁教授的药物配伍和处方进行分析。结果 本研究利用复杂网络分析方法获得了丁教授治疗房颤的核心处方，提示益气活血解毒法是其主要治则治法；利用处方相似性和社团分析方法，获得15组类方，其中3种类方与丁教授总结的三大治法高度符合；为探寻丁教授清热解毒配伍特点，结合关联规则和点式互信息算法，获得了10个丁教授清热解毒配伍药对。结论 数据挖掘技术提供了名医处方数据分析与提炼的可行方法，对丁教授经验的传承和临床应用提供直接可靠的依据。