我国化学药品申报资料中关于生产线相关要求的审评考虑

目的药品的生产场所是为满足药品生产要求的一系列生产要素的组合,其既是药品生产的硬件条件,也是注册申报时审评的物质基础。笔者旨在初步探讨我国化学药品申报资料中生产线的内涵、外延,以期为规范药品注册申报提供一定的参考。方法在梳理我国化学药品申报资料中关于生产场所信息的历次要求的基础上,结合日常药学审评工作以及具体案例进行分析。结果与结论应明确申报资料中拟定生产线的内涵及边界,强化不同监管部门之间的有效沟通,及时更新相关证明性信息,同时还应持续关注我国关于生产线相关变更的法律法规修订进展。     

Evolving insights: how DNA repair pathways impact cancer evolution

Viewing cancer as a large, evolving population of heterogeneous cells is a common perspective. Because genomic instability is one of the fundamental features of cancer, this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation, development, metastasis, and relapse. With the increased mutation rate and abundant diversity of the gene pool, this heterogeneity leads to cancer evolution, which is the major obstacle in the clinical treatment of cancer. Cells rely on the integrity of DNA repair machineries to maintain genomic stability, but these machineries often do not function properly in cancer cells. The deficiency of DNA repair could contribute to the generation of cancer genomic instability, and ultimately promote cancer evolution. With the rapid advance of new technologies, such as single-cell sequencing in recent years, we have the opportunity to better understand the specific processes and mechanisms of cancer evolution, and its relationship with DNA repair. Here, we review recent findings on how DNA repair affects cancer evolution, and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.     

Aflibercept in Combination With FOLFIRI as First-line Chemotherapy in Patients With Metastatic Colorectal Cancer (mCRC): A Phase II Study (FFCD 1302)

BackgroundFOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line.Patients and MethodsPatients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H₀: 55% and H₁= 75%. Data were analyzed in intention to treat.ResultsForty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification.ConclusionAlthough the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.     

花宝金运用抗癌解毒药对治疗肿瘤经验探析

导师花宝金教授长期从事中西医结合肿瘤的临床与基础研究。认为"正气内虚"是肿瘤发生的根本,"癌毒"是肿瘤发生的必要条件。收集导师多年临床组方,归纳、总结后发现清热解毒或攻毒散结之法常贯穿于始终。结合现代药物理论及导师多年临床经验,总结出临床常用七组抗癌解毒药对:(1)夏枯草、半枝莲;(2)石见穿、猫爪草;(3)金荞麦、蒲公英;(4)龙葵、白英、白花蛇舌草;(5)山慈菇、浙贝母;(6)藤梨根、蛇莓;(7)全蝎、蜈蚣。通过整体与局部的辨病与辨证、根据肿瘤的不同类型及发病阶段,结合癌毒的病机特点,灵活运用抗癌解毒药对,临床疗效确切。     

2014—2018年天津市肿瘤医院门诊麻醉性镇痛药的使用情况分析

目的 分析2014—2018年天津市肿瘤医院门诊麻醉性镇痛药的使用情况，为临床合理使用提供参考。方法 调取天津市肿瘤医院2014—2018年门诊麻醉性镇痛药的用药相关信息，对药物剂型、使用金额、用药频度（DDDs）、日均费用（DDC）及药品排序比（B/A）进行统计分析。结果 2014—2018年门诊麻醉性镇痛药中，口服剂型的使用金额和DDDs的构成比逐年上涨，透皮贴剂和注射剂使用金额和DDDs的构成比呈下降趋势。硫酸吗啡缓释片30 mg的DDDs排名一直居于首位，羟考酮缓释片10 mg在2016年后上升至第2位，羟考酮缓释片40 mg排名大幅上升，芬太尼透皮贴剂8.4 mg的DDDs排名出现明显下降。2016—2017年各麻醉性镇痛药的DDC开始略有下降。各药品的B/A略有变化，均接近1，表明使用金额与使用频度的同步性较好。结论 天津市肿瘤医院麻醉性镇痛药的使用合理，符合安全、有效、方便的原则。     

基于计算机辅助药物设计的清肺排毒汤多靶点系统治疗新型冠状病毒肺炎(COVID-19)物质基础探究

目的通过对清肺排毒汤功效和新型冠状病毒肺炎(COVID-19)病机的分析,基于计算机辅助药物设计(CADD)从多靶点结构出发系统探索清肺排毒汤排毒、抑制炎症风暴、利水渗湿3个方面的物质基础和分子机制。方法 TCMSP下载清肺排毒汤成分,基于血管紧张素转化酶II(ACE2)、白细胞介素-6受体(IL-6R)和水通道蛋白(AQP)分别进行分子对接虚拟筛选并对其结合模式进行分析。对利水药白术、茯苓、猪苓、泽泻进行反向靶点预测和GO分析和KEGG通路富集分析,预测其作用机制。结果阻断病毒作用最突出的前3位中药为甘草、麻黄、枳实,抑制炎症作用最突出的前3位中药是甘草、柴胡、紫菀;清肺排毒汤4个子方中,小柴胡汤阻断病毒、抑制炎症风暴的潜在活性化合物数均排第1。槲皮素及其衍生物对ACE2和IL-6R2个靶点均具有较强结合能力,是潜在的双靶点活性化合物。ACE2的Lys353残基是化合物与ACE2结合的关键位点。白术、茯苓、猪苓、泽泻缺乏阻断病毒、抑制炎症风暴的化合物,分子对接结果显示,这4味药材中含有的东莨菪内酯、去氢齿孔酸、α-D-半乳糖、环氧泽泻烯具有与水通道蛋白4(AQP4)的潜在结合能力。结论清肺排毒汤可通过多种化合物分别与ACE2、IL-6R、AQP4结合,发挥排毒、抑制炎症风暴、利水渗湿的作用;各组成子医方配伍合理,通过多点协同、优势互补发挥防治作用;得到了中药阻断新型冠状病毒(SARS-Co V-2)成分关键的结合位点Lys353,为清肺排毒汤药效机制的多角度挖掘和单体成分的现代化开发提供线索。