靶向MLL1-WDR5蛋白-蛋白相互作用抑制剂的研究进展

Mixed lineage leukemia 1(MLL1)是组蛋白甲基转移酶SET家族的成员之一。MLL1与WDR5、RbBP5、Ash2L和DPY-30组成MLL1甲基转移酶复合物调控组蛋白H3的第4位赖氨酸的甲基化水平，对造血系统的发育和血细胞的更新至关重要。部分白血病患者体内存在因MLL1基因易位而产生的致癌蛋白——MLL1融合蛋白，MLL1融合蛋白在发挥其致癌作用时需要功能完整的MLL1酶复合物，故靶向MLL1-WDR5的蛋白-蛋白相互作用成为治疗MLL1融合型白血病的潜在策略。本文对MLL1-WDR5蛋白-蛋白相互作用的生物学机制、结构信息以及抑制剂进行了系统的总结，并结合已报道数据对该领域进行了展望，以期为后续研究提供参考。     

Current Trends in API Co-Processing: Spherical Crystallization and Co-Precipitation Techniques

Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.     

欧洲药物战略（2020）及其对中国医药领域的启示

在当前国际制药技术出现重大创新和变革、药品研发技术信息化和数字化程度不断发展，以及新型冠状病毒肺炎（COVID-19）疫情大流行的背景下，欧盟委员会为满足未竟临床需求、激励行业创新、增强监管系统应变能力、巩固欧盟药品监管体系国际地位，于2020年底发布了《欧洲药物战略》（Pharmaceutical Strategy for Europe，PSE）。PSE被视为欧洲未来5年卫生政策的“基石”，对欧洲制药领域发展和管理具有重要指导意义。通过对PSE制定背景及发展战略目标、具体举措等内容进行梳理分析，并结合中国COVID-19疫情防控与行业发展、药品科学监管与鼓励创新等实际工作提出政策建议。     

An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.     

淫羊藿（苷）对男性生殖系统的作用和机制

淫羊藿是一种常用的中药材,淫羊藿苷是从淫羊藿中提取的一种黄酮类化合物,也是淫羊藿中最主要的活性物质。研究发现,淫羊藿苷具有促进成骨细胞的生成和活化、调节免疫、抗衰老和抗炎等多种功能。临床上淫羊藿（苷）用于治疗生殖系统、骨关节系统、呼吸系统、神经系统、心血管系统和免疫系统等多种疾病。淫羊藿（苷）对男性生殖系统的作用及机制主要包括具有雄性激素样作用,促进睾内睾酮的合成和分泌。淫羊藿（苷）通过改善精子发生的微环境、增强睾丸抗氧化作用促进精子生成,增加精子密度,改善精子活力,减缓生殖衰退。此外,淫羊藿（苷）可促进阴茎勃起,治疗勃起功能障碍及早泄。     

Transdermal Delivery of Insulin Using Combination of Iontophoresis and Deep Eutectic Solvents as Chemical Penetration Enhancers: In Vitro and in Vivo Evaluations

A serious challenge in transdermal iontophoresis (IP) delivery of insulin (INS) is the low permeability of the drug across the skin. In this paper, we introduced deep eutectic solvent (DESs) as novel chemical penetration enhancers (CPEs) for transdermal IP of INS across rat skin, both in vitro and in vivo. Three different DESs based on choline chloride (ChCl), namely, ChCl/UR (ChCl and urea), ChCl/GLY (ChCl and glycerol), and ChCl/EG (ChCl and ethylene glycol) in the 1:2 molar ratios have been prepared. To evaluate the capability of studied DESs as CPEs for IP delivery of INS, the rat skin sample was treated with each DES. The effects of different experimental parameters (current density, formulation pH, INS concentration, NaCl concentration, and treatment time) on the in vitro transdermal iontophoretic delivery of INS were investigated. The in vitro permeation studies exhibited that INS was easily delivered employing ChCl/EG, and ChCl/GLY treatments, compared with ChCl/UR: the cumulative amount of permeated INS at the end of the experiment (Q_24h) was found to be 131.0, 89.4, and 29.6 µg cm⁻² in the presence of ChCl/EG, ChCl/GLY, and ChCl/UR, respectively. The differences in Q_24h values of INS are due to the different capabilities of the studied DESs to treat the epidermis layer of skin. In vivo experiments revealed that the blood glucose level in diabetic rats could be decreased using ChCl/EG, and ChCl/GLY as novel CPEs in the IP delivery of INS. The presented work will open new doors towards searching for novel CPEs in the development of transdermal IP of INS.     

Forced Oxidative Degradation Pathways of the Imidazole Moiety of Daclatasvir

Daclatasvir hydrochloride (DCV) is the active pharmaceutical ingredient of Daklinza, a marketed product for the treatment of hepatitis C viral infection. The intrinsic stability of daclatasvir was evaluated via a forced degradation study. DCV was found to be stable in the solid state. In solution, its carbamate moiety is susceptible to basic hydrolysis, whereas its imidazole is liable to base-mediated autoxidation to form degradants 1 and 3, 7-8, respectively. The imidazole moiety can also be oxidized to form degradants 6-7 in the presence of hydrogen peroxide or azobisisobutyronitrile. The chloro-adduct degradant 9 was also observed in hydrogen peroxide solution. Furthermore, the imidazole moiety is sensitive to photodegradation in solution. Degradants 2-8 were observed in a solution of DCV exposed to high intensity light/UV light; the formation of degradants 2 and 5-8 was postulated through 4 degradation pathways. The degradants 3 and 4 were deemed to be secondary degradants of 7 and 5, respectively.     

基于UPLC-Q/TOF-MS分析淫羊藿炮制前后黄酮组分的变化规律

目的基于UPLC-Q/TOF-MS技术建立淫羊藿炮制前后指纹图谱,对其全成分进行分析并找出标志性化学成分,以明确淫羊藿炮制前后黄酮组分的变化规律。方法采用UPLC-Q/TOF-MS技术,在正离子模式下采集淫羊藿生品及炮制品样品数据,并在此基础上根据正交-偏最小二乘判别分析(OPLS-DA)整体探究9个不同产地、批次的淫羊藿炮制前后化学成分的差异。结果从淫羊藿生品及炮制品中寻找并鉴定出9个标志性化学成分,即8-乙烯-山柰酚、淫羊藿素、淫羊藿次苷I、淫羊藿素-3-O-葡萄糖苷、异戊醇基箭藿苷B、1,3-异戊二烯基朝藿定C、1,3-异戊二烯基-箭藿苷B-7-O-葡萄糖醛酸、3-O-(4-乙酰氧基)鼠李糖-2-O-(间二乙酰氧基)葡萄糖-淫羊藿苷及其同分异构体。结论淫羊藿炮制后黄酮组分结构发生变化,次级糖苷增加,多级糖苷减少,淫羊藿黄酮组分总体向低糖苷组分转化,进一步阐明了淫羊藿加热炮制后黄酮组分的变化规律。     

基于德尔菲法构建我国临床药师知识体系标准

目的：建立临床药师知识体系标准，为临床药师的培养和评估提供依据。方法：通过文献查阅，梳理出若干一级指标和二级指标；依据按Likert5级评分法设计咨询问卷；运用德尔菲法对35名专家进行两轮问卷咨询。结果：建立了包含5个一级指标，33个二级指标的临床药师知识体系标准。两轮咨询中，专家咨询积极系数分别为100%和92.9%，专家权威系数分别为0.904 3和0.907 7，专家协调系数分别为0.268和0.565。结论：专业核心知识是临床药师最应具备的知识，是临床药师培养的重中之重；临床药师的知识结构要由"以化学知识为主"转变为"以医学知识为主"；临床药师自身需要注重知识的再生，并树立终身学习的理念。本研究专家积极性和权威程度高，意见协调程度好，建立的知识体系标准能够对临床药师的培养与评估提供依据。     

英国价值定价理念对我国医保药品报销政策的启示

本文在梳理英国医保药品报销政策的基础上,通过对价值定价理念的深入研究和理解,系统探讨其在报销政策制定过程中对药品目录遴选、价值测算、支付标准确定、医保基金平衡和报销效益评估的作用机制,并深入思考通过价值定价理念建立起的药物警戒体系与药品报销政策间的衔接机制。在此基础上总结价值定价理念的特点、应用阶段和具体操作方法,以期为我国提供借鉴。