Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.     

以静脉药物配置中心为平台的静脉用药医嘱干预

目的 以静脉药物配置中心为平台,对用药医嘱进行分析和干预,提高用药医嘱的合理性,促进临床合理用药。方法 对静脉药物配置中心服务的6个病区用药医嘱中的不合理医嘱进行统计分析。结果 不合理医嘱明显减少,用药医嘱合理性大幅度提高差异有显著性（P＜0.01）。结论 通过对用药医嘱干预,能促进临床合理用药,保证患者用药安全。     

Antibacterial Potential of Garlic-Derived Allicin and Its Cancellation by Sulfhydryl Compounds

Allicin (allyl 2-propenethiosulfinate), an antibacterial principle of garlic, has drawn much attention, since it has potent antimicrobial activity against a range of microorganisms, including methicillin-resistant Staphylococcus aureus. There have been many reports on the antibacterial properties of allicin, but no quantitative comparison of antibacterial activities between freshly prepared garlic extract and clinically useful antibiotics has been performed. To verify the substantial antibacterial effect of aqueous garlic extract, we compared it with those of allicin and several clinically useful antibiotics using two representative bacteria commonly found in the human environment, Gram-positive S. aureus and Gram-negative Escherichia coli. The garlic extract had more potent anti-staphylococcal activity than an equal amount of allicin. In terms of antibiotic potency against Gram-positive and Gram-negative bacteria, authentic allicin had roughly 1–2% of the potency of streptomycin (vs. S. aureus), 8% of that of vancomycin (vs. S. aureus), and only 0.2% of that of colistin (vs. E. coli). The antibacterial activity of allicin was completely abolished by cysteine, glutathione and coenzyme A, but not by non-SH-compounds. The oxygen in the structure (–S(=O)–S–) of allicin therefore functions to liberate the S-allyl moiety, which might be an offensive tool against bacteria.     

甲基强的松龙联合中剂量环磷酰胺治疗重症肌无力危象的临床效果

目的:探究甲基强的松龙联合中剂量环磷酰胺(CTX)治疗重症肌无力危象(MGC)的临床效果及安全性。方法:选取2012年1月~2015年6月在我院神经内科就诊的MGC患者90例,随机分为对照组(45例)和观察组(45例),对照组患者接受甲基强的松龙治疗,观察组采用甲基强的松龙联合中剂量CTX治疗。比较两组患者的临床疗效及不良反应的发生情况。结果:观察组患者呼吸困难消失时间、吞咽功能恢复时间和肢体无力症状改善时间均明显短于对照组(P0.05);观察组用药7 d内治疗有效率86.7%明显高于对照组(P0.05),肺部感染发生率20%,较对照组显著降低,差异均具有统计学意义(P0.05)。结论:甲基强的松龙联合中剂量CTX可有效提高MGC的治疗效果,促进患者早日康复,且肺部感染的发生率降低。     

Platelet proteomics applied to the search for novel antiplatelet therapeutic targets

Introduction: Unwanted platelet activation is associated with numerous diseases, mainly thrombosis-related. In this context, proteomics has emerged as a novel tool with potential for drug target discovery and to scrutinize the effects of antiplatelet drugs.

Areas covered: The present review presents the main findings of platelet proteomic studies to date in the context of drug target discovery and perspectives for the future ahead. It includes data and evidences obtained from literature searches on PubMed as well as commentaries derived from the authors’ experience and opinions.

Expert commentary: Platelet proteomics applied to drug target discovery is a young field. Recent studies have shown promising data, especially in the context of coronary artery disease. However, challenges remain such as establishing definitive guidelines for blood collection and platelet isolation, essential to guarantee data reproducibility. Recent advances in quantitative platelet proteomics should lead to novel studies with higher clinical impact in the near future.     

非甾体抗炎药在骨科手术超前镇痛中的临床应用研究

目的:研究非甾体抗炎药的超前镇痛在骨科手术中的效果。方法:按照入选标准和排除标准选取2014年1月至2014年6月收治入院行骨科手术的各类骨折患者。记录每名患者人口统计学资料,骨折类型和部位,手术和麻醉方式,镇痛治疗方案,术前和术后疼痛评分,心理评分,用药期间不良反应,患者满意度评分。结果:本研究共纳入241名行骨折手术患者,分为超前镇痛组(n=115)和对照组(n=126),超前镇痛组术前使用非甾体抗炎药(主要为帕瑞昔布、塞来昔布)进行镇痛,对照组术前不使用非甾体抗炎药镇痛,两组术前疼痛评分无显著性差异。超前镇痛组和对照组在术后6 h、12 h、48 h、72 h视觉疼痛评分(visual analogue scale,VAS)、不良反应发生率和满意度评分差别有统计学意义(P0.05)。超前镇痛组心理评分低于对照组,不良反应发生率少于对照组,满意度较高。结论:非甾体抗炎药超前镇痛运用于骨科手术中,能够有效缓解手术切口疼痛,减轻炎症反应,减少不良反应的发生,患者满意度高。     

On the stability and biological behavior of cyclometallated Pt(IV) complexes with halido and aryl ligands in the axial positions

A series of cyclometallated platinum(IV) compounds (3a, 3a′ and 3b′) with a meridional [C,N,N′] terdentate ligand, featuring an halido and an aryl group in the axial positions has been evaluated for electrochemical reduction and preliminary biological behavior against a panel of human adenocarcinoma (A-549 lung, HCT-116 colon, and MCF-7 breast) cell lines and the normal bronquial epithelial BEAS-2B cells. Cathodic reduction potentials (shifting from −1.463 to −1.570 V) reveal that the platinum(IV) compounds under study would be highly reluctant to be reduced in a biological environment. Actually ascorbic acid was not able to reduce complex 3a′, the most prone to be reduced according its reduction potential, over a period of one week. These results suggest an intrinsic activity for the investigated platinum(IV) complexes (3a, 3a′ and 3b′), which exhibit a remarkable cytotoxicity effectiveness (with IC₅₀ values in the low micromolar range), even greater than that of cisplatin. The IC₅₀ for A-549 lung cells and clog P values were found to follow the same trend: 3b′ > 3a′ > 3a. However, no correlation was observed between reduction potential and in vitro activity. As a representative example, cyclometallated platinum(IV) compound 3a′, exercise its antiproliferative activity directly over non-microcytic A-549 lung cancer cells through a mixture of cell cycle arrest (13% arrest at G1 phase and 46% arrest at G2 phase) and apoptosis induction (increase of early apoptosis by 30 times with regard to control). To gain further insights into the mode of action of the investigated platinum(IV) complexes, drug uptake, cathepsin B inhibition and ROS generation were also evaluated. Interestingly an increased ROS generation could be related with the antiproliferative activity of the cyclometallated platinum(IV) series under study in the cisplatin-resistant A-549 lung and HCT-116 cancer cell lines.     

红豆杉高产悬浮细胞系建立及其紫杉醇诱导的研究进展

紫杉醇是一种四环二萜酰胺类化合物,是从红豆杉科红豆杉属植物中提取分离出来的次生代谢物,是世界公认广谱、活性强的天然抗癌新药。但直接从植物中提取紫杉醇的传统生产方式,不仅产量低,且会对野生红豆杉资源造成严重破坏,同时紫杉醇的化学全合成也由于其结构复杂而不具备商业价值。与之相反,细胞培养技术具有受外界影响少、生产成本低、次生代谢产物多、细胞生长周期短的优势,是目前最具前景的紫杉醇生产方式。近年来随着科研水平的不断提升,紫杉醇无论在生理代谢调控、关键基因挖掘,还是新药物制剂与剂型及其类似物的开发和运用等方面,都取得了进展,但要建立紫杉醇商业化高产体系,还必须和前人的研究经验相结合。该文对红豆杉高产悬浮细胞系建立及其紫杉醇诱导的研究进展进行了综述,主要包括前人对红豆杉属植物组织与细胞培养相关的外植体、培养基、激素、培养条件、褐化等问题的研究,以及从代谢调节、培养方式、基因工程等多方面提高紫杉醇含量的最新进展,最后总结了当前研究的不足,并对今后通过多种组合方式来提高紫杉醇含量的生产途径进行了展望。以期促进红豆杉组织培养技术的进步,为药用资源保护和利用提供一定的理论基础与生产指导。