批准用于奶牛的抗菌药物分析

我国奶牛养殖规模不断扩大,奶业产值比重逐步提高,给奶牛疫病防治带来巨大压力。奶牛乳房炎及细菌性肺炎等呼吸系统疾病和细菌性肠炎等消化系统疾病最为常见,抗菌药物的使用成为主要防治手段。但抗菌药物的不当使用易使细菌产生耐药性,增加临床治疗的成本和难度,危害我国奶牛产业发展。本文对截至2021年7月我国和美国、英国、日本、欧盟批准用于奶牛的抗菌药物产品进行整理、统计与分析,包括抗菌药物的分类、剂型以及适应证等,旨在为我国奶牛用抗菌药物管理、合理用药和新兽药开发提供参考。     

Hepatitis B virus infection reactivation in patients under immunosuppressive therapies: Pathogenesis,screening, prevention and treatment

With a 5.3% of the global population involved, hepatitis B virus (HBV) is a major public health challenge requiring an urgent response. After a possible acute phase, the natural history of HBV infection can progress in chronicity. Patients with overt or occult HBV infection can undergo HBV reactivation (HBVr) in course of immunosuppressive treatments that, apart from oncological and hem-atological diseases, are also used in rheumatologic, gastrointestinal, neurological and dermatological settings, as well as to treat severe acute respiratory syndrome coronavirus 2 infection. The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition. The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence. The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed. The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status. Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.     

Orphan drug development: The impact of regulatory and reimbursement frameworks

The enactment of orphan drug-specific legislation pioneered by the USA was subsequently followed by many regions, including the European Union (EU), Australia, Japan, and Taiwan. Here, we discuss the associated regulations established and their impacts in the aforementioned regions, which are among the first with frameworks specific for orphan drugs. Varied scopes of rare diseases or orphan drugs, diverse incentives, and heterogeneous types of reimbursement systems imply the prioritization of the agencies concerned. The numbers of designated and approved drugs reflect the impact of the regulatory and reimbursement frameworks. A comparison of the frameworks and their impact in the respective regions could provide valuable information for developing and improving related frameworks for countries worldwide.     

Metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) by Streptomyces griseolus CYP105A1 and its variants

In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4′-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3′-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4′-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites.     

Differences in Evidentiary Requirements Between European Medicines Agency and European Health Technology Assessment of Oncology Drugs—Can Alignment Be Enhanced?

ObjectivesNational health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies’ evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.MethodsInterviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.ResultsAcceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.ConclusionsDifferences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.     

改良经椎间孔入路及后路腰椎椎间融合术治疗中老年轻中度腰椎滑脱症疗效比较

目的比较改良经椎间孔入路腰椎椎间融合术（transforaminal lumbar interbody fusion，TLIF）与后路腰椎椎间融合术（posterior lumbar interbody fusion，PLIF）治疗中老年轻中度腰椎滑脱症的手术疗效。方法回顾分析 2015 年 1 月—2017 年 1 月收治的符合选择标准的 106 例轻中度腰椎滑脱症（Meyerding 分度≤Ⅱ度）患者临床资料，根据手术方式不同分为改良 TLIF 组（54 例）及 PLIF 组（52 例）。两组患者性别、年龄、病程、滑脱椎体、Meyerding 分度及滑脱类型等一般资料比较，差异均无统计学意义（P>0.05）。记录并比较两组术中出血量、手术时间、术后引流量、术后卧床时间、住院时间、并发症等围术期相关指标。术前及术后 1 周，1、6、12 个月，末次随访时采用疼痛视觉模拟评分（VAS）和日本骨科协会（JOA）评分评价疼痛及功能改善情况，术前与末次随访时测量滑脱角与椎间隙高度评价椎体滑脱矫正情况，末次随访时根据 Suk 标准判定椎间融合情况。 结果所有患者均获随访，随访时间 A 组 25～36 个月，平均 32.7 个月；B 组 24～38 个月，平均 33.3 个月。改良 TLIF 组术中出血量、手术时间、术后引流量、术后卧床时间和住院时间均显著少于 PLIF 组（P<0.05）。两组患者术后各时间点 VAS 评分和 JOA 评分均较术前显著改善（P<0.05）；术后 1、6 个月改良 TLIF 组 VAS 评分和 JOA 评分显著优于 PLIF 组（P<0.05）。两组患者末次随访时滑脱角及椎间隙高度均较术前显著改善（P<0.05）；术前及末次随访时两组间滑脱角及椎间隙高度比较差异均无统计学意义（P>0.05）。末次随访时根据 Suk 标准，改良 TLIF 组椎间融合率为 96.3%（52/54），PLIF 组为 98.1%（51/52），两组比较差异无统计学意义（χ²=0.000，P=1.000）。并发症：两组患者切口感染、肺部感染及术后 1 周内健侧神经损伤发生率比较差异均无统计学意义（P>0.05）；改良 TLIF 组均未发生术中硬脊膜损伤及术后 1 周内患侧神经损伤，PLIF 组分别发生 4 例（7.7%，P=0.054）和 8 例（15.4%，P=0.002）。 结论改良 TLIF 与 PLIF 手术治疗中老年轻中度腰椎滑脱症疗效肯定，改良 TLIF 手术对脊柱后柱正常结构损伤小、出血量和引流量少，硬脊膜和神经损伤发生率低，可改善术后疼痛，促进患者术后快速康复。     

哮喘相关基因与治疗药物的生物信息学分析

目的:通过生物信息学技术比较哮喘患者与健康人的基因芯片数据,初步鉴定与哮喘相关的基因以及治疗哮喘的潜在药物。方法:从基因表达数据库下载GSE74986基因芯片,使用GEO2R分析得出差异表达基因,采用Morpheus制作差异表达基因的热图;通过DAVID 6.8对差异表达基因进行基因本体及京都基因与基因组百科全书分析,使用String 10.5构建蛋白质-蛋白质相互作用网络,筛选核心基因。进一步使用Cytoscape 3.6.1的插件MCODE对差异表达基因进行模块分析。通过医学本体信息检索平台筛选治疗哮喘的小分子药物。结果:筛选出510个差异表达基因,包括29个上调基因和481个下调基因。差异表达基因生物过程与通路主要富集在染色质沉默、核糖核酸聚合酶Ⅱ启动子的转录调节、蛋白质转运、信使核糖核酸加工、核糖核酸剪接以及泛素介导的蛋白水解、内质网中的蛋白质加工、核糖核酸转运、髓样分化因子依赖性Toll样受体信号通路、血小板激活、核苷酸结合寡聚化结构域样受体信号通路等。共得出9个核心基因,包括T-复合蛋白1θ亚基(CCT8),T复合物蛋白1α亚单位(TCP1),26S蛋白酶调节亚单位S10B(PSMC6),热休克蛋白90α(HSP90A) A1,细胞周期蛋白C(CCNC),HSP90AB1,26S蛋白酶体非ATP酶调节亚基6(PSMD6),泛素特异性蛋白酶14(USP14),真核细胞翻译起始因子4E(EIF4E)。得出2个重要模块,模块里的基因主要涉及剪接体和泛素介导的蛋白水解、蛋白修饰以及核糖核酸修饰等生物过程。治疗哮喘的潜在小分子药物有茴香霉素和金雀异黄素等。结论:差异表达基因和核心基因促进了对哮喘发病分子机制的理解,为哮喘的诊治提供了潜在的基因靶标与治疗药物。     

National comprehensive cancer network recommendations for drugs without US food and drug administration approval in metastatic breast cancer: A cross-sectional study

BackgroundNational Comprehensive Cancer Network (NCCN) guidelines can include recommendations for off-label use of anti-cancer drugs. Here, we evaluate NCCN recommendations not supported by US Food and Drug Administration (FDA) approval and explore associations with such recommendations.MethodsAll NCCN recommendations for MBC and their supporting data were identified. Drug labels were reviewed to determine whether recommendations are FDA approved. Logistic regression was used to compare FDA approved and off-label recommendations for pre-specified categories, including drug type, tumor subtype, level of recommendation and line of therapy.ResultsOf 124 recommendations identified, 68 (55%) were off-label. Chemotherapy and human epidermal growth factor receptor 2 (HER2) targeted drugs were associated with lower odds of FDA approval (OR = 0.28, p = 0.001 and OR = 0.29, 95% p = 0.005, respectively). Recommendations for endocrine therapy (OR = 3.44, p = 0.009) and non-HER2 targeted treatment (OR = 10.0, p < 0.001) were more commonly FDA approved indications. Compared to combination therapies, monotherapies were more likely to be FDA approved (OR = 3.45, p = 0.001) as were category 1 (OR = 7.63, p = 0.001) and preferred NCCN recommendations (OR = 4.07, p < 0.001). Compared to off-label recommendations, NCCN recommendations of approved drugs were based on significantly higher sample size (mean 477 vs. 342 patients, p = 0.02) and were non-significantly associated with availability of randomized data (OR = 2.0, 95% CI 0.89–4.49, p = 0.09).ConclusionMore than half of all NCCN recommendations for MBC are off-label, mostly involving chemotherapy containing regimes for HER2 negative disease and combinations which include HER2-targeted drugs. Improved transparency of NCCN guidelines may result from reporting of the strength of the evidence supporting recommendations for MBC.     

心房颤动射频消融术后心脏损伤后综合征1例治疗心得及文献复习

对我院心脏中心2018年5月诊断的1例心房颤动射频消融术后心脏损伤后综合征的临床资料进行回顾性分析,并对国内外相关文献进行复习。患者RFCA术后早期出现胸腔积液、炎性标志物升高,拟诊断为RFCA术所致心脏损伤后综合征(postcardiac injury syndrome,PCIS),应用皮质类固醇激素后胸腔积液吸收。PCIS患者一般情况下预后良好。有明显发热、胸痛症状的患者,可予非甾体类消炎镇痛药物(如吲哚美辛)等对症处理。早期应用皮质类固醇激素对有心包积液和胸腔积液的患者有良好的治疗效果。     

臀部筋膜脂肪瓣修复坐骨结节和大转子复发性窦道型压疮

目的总结臀部筋膜脂肪瓣修复坐骨结节、大转子复发性窦道型压疮的效果。方法2018 年 2 月—2019 年 6 月，收治 12 例 13 处长期截瘫伴坐骨结节、大转子复发性窦道型压疮患者。其中男 10 例 11 处，女 2 例 2 处；年龄 46～56 岁，平均 51 岁。截瘫 10～20 年，平均 13 年；所有患者均有压疮手术史，术后 3 个月～12 年复发。其中坐骨结节处压疮 11 例，坐骨结节合并大转子处压疮 1 例。创面清创、切除窦道假性滑液囊，采用单侧或双侧臀部筋膜脂肪瓣填塞窦道，术区一期缝合闭合切口。结果术后 13 处压疮切口均Ⅰ期愈合，局部无红肿、渗液，术后 14 d 拆线出院。术后局部平坦，外观理想。术后患者均获随访，随访时间 8～24 个月，平均 14 个月。随访期间压疮均无复发。结论臀部脂肪组织丰富，利用筋膜脂肪瓣修复坐骨结节、大转子复发性窦道型压疮设计、操作简便，临床效果良好。