医院建立药品卫生检验室的实践

《无菌检查法》和《微生物限度检查法》已载入1995年版《中毕人民共和国药典》。无菌检查法系指检查药品与敷料是否无菌的一种方法。微生物限度检查法是指非规定灭菌制剂及其原、辅料受到微生物污染程度的一种检查方法,包括染菌量及控制菌的检查。国家卫生部颁（86）卫药字第81号《药品卫生标准》于1987年12月1日起供内部执行,卫药字（8）第50号文《药品卫生标准补充规定和说明》对中药和含中药及化学药的复合制剂的卫生标准作了补充规定。对中药（口服药品、外用药品等）、化学药品及生化药品的卫生标准作出了规定。上述规定,《中国人民…     

药品生产质量管理规范（2010年修订）检查指南

（接9月下） 61．最终灭菌的无菌药品：指采用最终灭菌工艺的无菌药品。（药品GMP,无菌药品附录,第4条） 药品生产质量管理规范（2010年修订）检查指南相关法规摘录《中华人民共和国药品管理法》 （主席令第45号）节选 在药品GMP检查过程中,以下要求应予以关注。 第九条 药品生产企业必须按照国务院药品监督管理部门依据本法制定的（《药品生产质量管理规范》组织生产。药品监督管理部门按照规定对药品生产企业是否符合《药品生产质量管理规范》的要求进行认证;对认证合格的,发给认证证书。     

美国FDA药品质量控制微生物实验室检查指南

值此2000年版药典出版发行、执行之际,为了更好地理解药典中无菌和微生物限度检查法的增、修订内容;了解药品微生物质量控制在制药行业及质量检验中的重要性;以及今后发展的方向,特将美国FDA《药品质量控制微生物实验室检查指南》一文翻译推荐给大家。通过该文,可以了解和借鉴FDA的一些先进的观点。如:对化学、生化药品是否需要进行微生物限度检查?如何评价微生物污染在非无菌药品中的重要性。制订非无菌药品微生物限度的原则。无菌和微生物限度检查的培养时间、初试阳性结果后,是否复试及如何复试的规定。微生物实验中建立阳性、阴性对照的重要性。参加检查或验收微生物实验室时应重视和注意的问题等。     

福建省使用的口服化学药品最小销售单元现状分析

目的：通过调查分析福建省上市药品口服制剂最小销售单元现状,为调整药品包装规格提供参考。方法：以《国家基本医疗保险、工伤保险和生育保险药品目录（2021年）》中的化学药品口服制剂为研究对象,选取福建省药械联合限价阳光采购平台数据,利用SPSS19.0进行数据处理与分析。结果： 检索到口服制剂949个,装量范围为1~500片（粒或丸）,使用天数范围为0.4~66.7天。装量和使用天数中位数M（P25,P75）分别为20（10,30）、7.2（4.7,13.3）。普通药品、慢性病用药和特殊药品在装量和使用天数上存有统计学差异（P＜0.001）。“集采”药品较非“集采”药品装量更大,使用天数更长,两者有统计学差异（P＜0.05）。销售金额排名前20位的口服制剂装量分布在5~50片（粒或丸） 之间,使用天数1~30天不等,其中87.5%的慢性病用药使用天数均＜14天。结论：上市药品慢性病用药 （心血管系统、内分泌系统、血液系统用药、抗肿瘤药及免疫调节剂等）装量普遍过小,普通药品（全身激素制剂,泌尿生殖系统药和性激素,肌肉-骨骼系统用药）及特殊药品（第一类、第二类精神药品）装量偏大。建议普通药品最小销售单元装量采用＜7天使用量小包装,慢性病用药采用4周使用量的倍量包装,特殊药品（精神药品、麻醉药品）采用特殊装量包装。     

化学药品注射剂的灭菌或无菌工艺现行要求及考虑

化学药品注射剂是临床上应用较广的一类无菌药品，鉴于其较高的安全性风险，确保注射剂的无菌性尤为关键。结合中国、美国和欧盟对注射剂的无菌保障监管及药品生产质量管理规范（GMP）指南的现行要求，进一步探讨化学药品注射剂的灭菌或无菌工艺控制。目前，我国化学药品注射剂的灭菌或无菌工艺选择要求与欧美国家基本一致，美国和欧盟对于湿热灭菌注射药品已实施参数放行。通过阐述注射剂灭菌或无菌工艺的评估及研究，为制药企业化学药品注射剂无菌保障控制策略及无菌风险管控的不断完善提供参考，以更好地提高注射剂的无菌保障。     

河南省药品生产企业《药品生产质量管理规范》符合性检查情况分析

目的 规范药品生产企业安全、合规生产，为药品监督管理部门制订监管措施提供参考。方法 统计并分析河南省2020年5月至2021年11月在对172家次高风险药品生产企业《药品生产质量管理规范》（GMP）符合性检查中发现的缺陷项目，并有针对性地提出改进措施与建议。结果 共发现缺陷项目1 028项，其中主要缺陷26项，一般缺陷1 002项，严重缺陷0项。涉及缺陷条款1 045条次，主要分布于质量控制与质量保证（19.23%）、文件管理（17.89%）、设备（17.03%）、确认与验证（6.03%）、物料与产品（5.93%）、附录中的无菌药品（5.93%）。生物制品、无菌药品（注射剂、滴眼剂、眼膏剂、无菌原料药）、毒性饮片生产企业分别发现缺陷项目62项、682项、269项，分别涉及缺陷条款66条次、687条次、270条次。结论 在执行GMP过程中，药品生产企业应强化质量控制与质量保证体系的管理，建立并完善文件管理体系，加强全过程培训，做好厂房设施设备的日常使用及维护；药品监督管理部门应持续优化资源配置，提升科学监管能力。     

水分活度与非无菌药品微生物控制

目的：通过控制非无菌药品的水分活度来控制微生物。方法：通过水分活度的概念和各种微生物的最低生长水分活度寻找控制微生物的途径。结果与结论：通过干燥除水、剂型改造、添加组分和降低温度等方法降低水分活度来提高非无菌药品的稳定性。     

基于监测网络的东莞市医疗机构急(抢)救药品供应保障体系构建与实践

目的：制定全市急（抢）救药品供应保障体系,探讨其对全市医疗机构急（抢）救药品缺乏以及费用的影响。方法：在全市16家各级不同医疗机构建立急（抢）救药品监测网络,通过制定急（抢）救药品储备目录、采购与调用管理规定、费用结算管理规定,以及建立常备化的储备点等多项措施构建供应保障体系。分别选取2017年1月至6月和2018年1月至6月全市医疗机构急（抢）救药品保障供应情况为对照组和试验组。观察保障体系实施前后,全市各级医疗机构急（抢）救药品缺乏的品种数、报损的品种数和费用以及采购费用。结果：实施该保障体系后,与对照组相比,试验组急（抢）救药品缺乏的品种数显著下降（P < 0.05）,而报损品种数、报损费用和采购费用也均显著下降（P < 0.05）。结论：急（抢）救药品供应保障体系,可有效改善医疗机构急（抢）救药品缺乏的状况,降低了报损费用和采购费用,具有进一步推广应用的价值。     

基本药物价格上涨的现况调查及因素分析-基于合肥某三级综合医院的调查

目的：探索公立医疗机构基本药物供应价格现状,分析药品价格上涨原因,为该领域的相关研究提供参考。方法：收集安徽省某三级综合性医院2016年1月1日-2017年9月30日期间内价格上涨的基本药物,用DDDc（药品日均费用）反映涨价药品对患者负担的影响,并通过咨询采购主管及联系药品经营商来调查药品涨价原因。结果：样本点在调查期间共使用1243种药品、366种国家基本药物及840种省基本药物。调查发现共有91种省基本药物（包括64种国家基本药物）在调查期间发生价格增长;DDDc涨幅为1.30元人民币,涨幅前20名的基本药物有17种为针剂,DDDc涨幅均大于7元人民币。导致药品涨价的主要原因有原辅料价格上涨、生产成本上涨、原供应生产企业无法供应、生产厂家供应价格上涨、配送企业供应价格上涨、配送企业无法供应和原配送企业无法满足“两票制”要求。结论：我国正致力解决人民群众用药贵的问题;但是,药品价格在招标后的上涨与我国医疗卫生体制改革及基本药物制度的目的相悖。因此,本研究建议我国继续完善药品招标制度,制定合理的定价机制及科学的补偿机制,充分发挥基本药物在使用中价格相对低廉的作用。     

浅析无菌药品的参数放行

目的:为提高我国无菌药品的质量控制水平提供参考。方法:通过对比传统的无菌检查质量控制方法,参考发达国家的参数放行指南,分析无菌药品参数放行优越性及具体实施方法。结果与结论:对于无菌药品,参数放行能够为最终产品提供更高水平的质量保证,其替代传统的质量控制方法是必然的趋势。     

Comparason of extraction methods for PCR detection of <Emphasis Type="Italic">Burkholderia cepacia</Emphasis> complex (BCC) from cystic fibrosis patients

Direct detection of Burkholderia cepacia complex (BCC) and its genomovars from sputum by molecular tests emerges as a method for rapid identification. In this study, four DNA extraction methods were evaluated for the identification for BCC from sputum of CF patients. Sputa from 28 CF patients were aliquoted and spiked with BCC reference strain. Boiling, phenol-chloroform, CTAB methods and a commercial spin column kit was used for DNA extraction. Total DNA yields were determined by spectrophotometry and single-round recA PCR was used for detection of BCC. No significant difference was observed in DNA yields from different extraction methods. Lower limit of detection for recA PCR was determined as 10⁶ cfu/ml. Amplification was observed in 7/16 (43.7%) of sputa for boiling, 8/16 (50%) of sputa for CTAB and 13/16 (81.2%) of sputa for phenol-chloroform method and spin column kit in the assay sensitivity range determined in the study. Phenol-chloroform and commercial spin column kit were found to be better suited for DNA purification from sputum of CF patients for BCC identification. Diagnostic impact of single-round recA PCR directly from sputum was limited to chronically-infected patients.     

P53和Bcl-2蛋白在基底细胞癌中的表达及临床意义

目的：探讨P53、B细胞淋巴瘤/白血病-2基因（bcl-2）蛋白在基底细胞癌（BCC）组织中的表达及临床意义。方法用免疫组化链霉素抗生素蛋白-过氧化物酶连结（SP）法检测P53、Bcl-2蛋白在40例BCC（BCC组）组织中的表达,以20例正常皮肤组织作为对照组。结果 P53、Bcl-2蛋白在BCC组表达阳性率分别为55%（22/40）、85%（34/40）,在对照组表达阳性率分别为15%（3/20）、10%（2/20）。P53、Bcl-2蛋白在BCC组中的表达明显强于对照组,差异有统计学意义（χ2=6.35、7.45,P＆lt;0.01）。结论 P53、Bcl-2蛋白的异常表达与BCC相关,说明其可能在BCC的发生及发展过程中起重要作用。     

Basal cell carcinoma: a paradigm for targeted therapies

Introduction: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012.

Areas covered: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials.

Expert opinion: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary.     

Discovery and preclinical development of vismodegib

Introduction: Vismodegib is the first Hedgehog (Hh) pathway inhibitor approved in the US for the treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC). It was approved by the US FDA on 30 January 2012, and by the European Commission on 12 July 2013, for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. Vismodegib selectively inhibits the Hh signaling pathway, binding to and inhibiting a critical signal-transducing component of the pathway, Smoothened (SMO). Vismodegib was discovered by Genentech, Inc., under a collaboration agreement with Curis, Inc.

Areas covered: This article reviews the development of vismodegib from its discovery, preclinical pharmacology and validation to the clinical pharmacokinetics and validation in Phase I and II clinical investigations. We also provide a survey of other Hh pathway inhibitors in clinical development.

Expert opinion: The authors’ experience in target-based drug discovery suggests that vismodegib’s path to the clinic deserves some reflection to identify key steps that have contributed to its success. Targeting the Hh pathway with vismodegib blocks the abberant signaling caused by mutational inactivation of the negative regulator PTCH1 or mutational activation of SMO. Vismodegib gives physicians a treatment option for patients with locally advanced or metastatic BCC for whom surgery or radiation is not recommended.     

Resistance of the Burkholderia cepacia complex to fosmidomycin and fosmidomycin derivatives

The Burkholderia cepacia complex (BCC) is a group of 17 closely related opportunistic pathogens that are able to infect the respiratory tract of cystic fibrosis patients. BCC bacteria are intrinsically resistant to many antibiotics and are therefore difficult to eradicate. Fosmidomycin could be a new therapeutic agent to treat BCC infections as it inhibits 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the non-mevalonate pathway essential in BCC bacteria for isoprenoid synthesis. In this study, the antimicrobial activity of fosmidomycin and eight fosmidomycin derivatives towards 40 BCC strains was investigated. All BCC strains were resistant to fosmidomycin, although addition of glucose-6-phosphate reduced the minimum inhibitory concentration values of FR900098, the fosmidomycin acetyl derivative, from 512 mg/L to 64 mg/L for Burkholderia multivorans and B. cepacia. This enhanced activity was linked to increased expression of the genes involved in glycerol-3-phosphate transport, which appears to be the only route for fosmidomycin import in BCC bacteria. Furthermore, upregulation of a fosmidomycin resistance gene (fsr) encoding an efflux pump was observed during fosmidomycin and FR900098 treatment. These results strongly suggest that the observed resistance in BCC bacteria is due to insufficient uptake accompanied by fosmidomycin and FR900098 efflux.     

Effect of non‐steroidal anti‐inflammatory drugs on non‐melanoma skin cancer incidence in the SKICAP‐AK trial

Recent studies link the prostaglandin metabolic pathway to skin carcinogenesis expanding possibilities that cyclooxygenase (COX) inhibitors may be utilized in non‐melanoma skin cancer (NMSC) chemoprevention. Using data from a study of the efficacy of retinol supplementation on incidence of NMSC, we sought to determine the role of non‐steroidal anti‐inflammatory drugs (NSAIDs) in NMSC development. Cox proportional hazards models describe the relationship between NSAID use and time to first squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) among participants categorized by use pattern: continuous users (use for length of study duration), new users (use for less than study duration), and non‐users. For SCC and BCC, there was a statistically significant protective effect for participants who reported use for less than the study duration (HR = 0.49, 95%CI 0.28–0.87 and HR = 0.43, 95%CI 0.25–0.73, respectively). Categorical examination of NSAIDs (aspirin (ASA) vs. non‐ASA NSAIDs) showed significant effects for BCC among those using non‐ASA NSAIDs for less than the study duration (HR = 0.33, 95%CI 0.13–0.80). For SCC and BCC, NSAID use of shorter duration and potentially more recent, was more protective than longer duration of use. These results are counter to the idea that longer duration of NSAID use is more protective. Additional investigations are needed into the role NSAIDs play in the chemoprevention of NMSC. Copyright © 2009 John Wiley & Sons, Ltd.     

栝楼不同药用部位质量控制的研究进展

瓜蒌子、瓜蒌皮、瓜蒌、天花粉来源于栝楼的不同药用部位,4味药材均为常用的大宗药材,现行版《中国药典》对其制定的质量标准过于简单,无法科学合理地控制其质量。本文对瓜蒌子、瓜蒌皮、瓜蒌、天花粉安全性和有效组分的研究进行综述,明确了相关研究存在的问题并针对问题提出建议,为科学全面的药材及饮片标准的制定提供参考依据。     

INHIBITION OF BOVINE CEREBRAL CORTEX PROSTAGLANDIN SYNTHETASE BY PHENOXYBENZAMINE AND CYPROHEPTADINE IN VITRO

1. Bovine cerebral cortex (BCC) microsomes were isolated from fresh brain using standard techniques. 2. Two a-adrenoceptor antagonists (phenoxybenzamine and phentolamine) and two anti-serotonin compounds (cyproheptadine and cinanserine) were compared with the anti-inflammatory drugs indomethacin and keptoprofene for inhibition in vitro of prostaglandin (PG) synthetase. 3. Phenoxybenzanine and cyproheptadine inhibited BCC PG synthetase in vitro, but their potency was 1% that of indomethacin and keptoprofene. Phentolamine and cinanserine did not inhibit PG synthetase in concentrations up to ten times the effective concentrations of the other test drugs. 4. It is suggested that the antipyrogenic effect of phenoxybenzamine and cyproheptadine may be due to their inhibitory effect on prostaglandin synthesis.     

Potentiation of startle response by d- and l-amphetamine: The possible involvement of pre- and postsynaptic alpha-adrenoreceptors and other transmitter systems in the modulation of a tactile startle response

The startle response to a metered puff of air was investigated in mice treated with d- and l-amphetamine and a range of drugs acting on central transmitter systems. d-Amphetamine produced a dose-related increase in startle response amplitude (SRA). l-Amphetamine was approximately twice as potent as d-amphetamine while apomorphine was without effect. Noradrenaline and alpha-methyl noradrenaline intracerebroventricularly (ICV), and clonidine IP, all tended to reduce control SRA but potentiated the effect of d-amphetamine. Apomorphine IP had no effect on control SRA or on the effect of d-amphetamine. Phenoxybenzamine, phentolamine and piperoxane reduced d-amphetamine potentiation at doses which had no significant effect on control SRA. Higher doses of phenoxybenzamine and phentolamine reduced control SRA. Yohimbine enhanced the effect of d-amphetamine but reduced control SRA. dl-Propranolol, d-propranolol and sotalol (MJ 1999) did not affect d-amphetamine potentiation. Pimozide was without effect on control SRA but caused a late potentiation of the effect of d-amphetamine. H44/68 and FLA 63 reduced d-amphetamine potentiation. Both 5-hydroxytryptamine (5-HT) ICV and p-chlorophenylalanine potentiated the effect of d-amphetamine. The predominant effect of arecoline, physostigmine and carbachol was also to potentiate d-amphetamine. Atropine enhanced and hyoscine reduced d-amphetamine potentiation. The results are discussed in terms of involvement in the startle response of a noradrenergic synapse possessing receptors resembling peripheral pre- and postsynaptic alpha-adrenoreceptors. Cholinergic and 5-HT systems may also be involved.     

MMP-9和Ⅳ型胶原在皮肤基底细胞癌和鳞状细胞癌中表达情况的初步探讨

目的通过检测MMP9和Ⅳ型胶原在皮肤基底细胞癌和鳞状细胞癌中的分布和表达,探讨皮肤基底细胞癌和鳞状细胞癌在恶性和侵袭性上的差异。方法用免疫组织化学染色SP法显示MMP9和Ⅳ型胶原在22例皮肤基底细胞癌、30例鳞状细胞癌和15例正常皮肤组织中的表达。结果MMP-9在皮肤基底细胞癌和鳞状细胞癌中的表达均有增强,而Ⅳ型胶原的表达均有减少。但两肿瘤之间差异无显著性。结论结合MMP-9表达的增强和Ⅳ型胶原表达的减少,表明MMP-9在肿瘤的侵袭及转移中起重要作用。