• 【2-取代-4-(3 ',4',5 '-三甲氧基苯基)-5-芳基噻唑类抗癌剂的合成及生物学评价。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.001 复制DOI
    作者列表:Romagnoli R,Baraldi PG,Salvador MK,Camacho ME,Preti D,Tabrizi MA,Bassetto M,Brancale A,Hamel E,Bortolozzi R,Basso G,Viola G
    BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.
    背景与目标: : 与微管蛋白结合并破坏微管动力学的抗肿瘤剂在过去几年中引起了极大的关注。为了扩展我们对噻唑环作为combretastatin A-4中存在的顺式烯烃的合适模拟物的了解,我们将3,4,5-三甲氧基苯基固定在噻唑核的C4-position。我们发现C2-和C5-positions的取代基对抗增殖活性具有深远的影响。比较噻唑环C5-position具有相同取代基的化合物,C2-position部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2)。相对于C2-amino对应物,N-甲基氨基取代基显着提高了MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基C2-position的空间体积增加导致活性降低1-2对数。2-n-甲基氨基噻唑衍生物3b,3d和3e是作为抗增殖剂的最具活性的化合物,其IC(50) 值从低微摩尔到个位数纳摩尔,此外,它们在多药耐药细胞系中也具有活性过表达P-糖蛋白。抗增殖活性可能是由化合物与微管蛋白聚合的秋水仙碱位点结合并破坏微管动力学引起的。此外,活性最高的化合物3e通过激活caspase-2,-3和-8诱导细胞凋亡,但3e并未引起线粒体去极化。
  • 【植物心理药物的临床试验。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(97)80050-5 复制DOI
    作者列表:Schulz V,Hübner WD,Ploch M
    BACKGROUND & AIMS: :Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.
    背景与目标: : 植物心理药物是对中枢神经系统具有刺激或镇静作用的植物提取物。植物心理药物是德国最常用的草药之一。一些制剂的疗效和无害化已通过高质量的临床试验确定。在1975年至1992年之间,共发表了34项临床研究,涉及约2326名患者,涉及银杏特殊提取物EGb 761和LI 1370的影响; 迄今为止,已对2120名患者进行了28项临床试验,其中包括圣约翰草的酒精提取物。卡瓦和缬草提取物的治疗功效已分别在六个和四个对照研究中进行了研究。一般来说,安慰剂效应可能很高,这就是为什么在这些研究中包括对照组是必不可少的。与合成精神药物相比,相当大的优势是副作用的发生率低,在安全性评估研究中,副作用的发生率低于3%。临床试验质量标准的急剧提高意味着只有少数制剂按照国际指南进行了大规模的测试计划。对于其他植物心理药物,由于现在要求的标准过高,因此存在无法进行进一步临床试验的危险。
  • 【抗微管剂对草履虫细胞培养生长的影响。】 复制标题 收藏 收藏
    DOI:10.1016/S0932-4739(11)80066-0 复制DOI
    作者列表:Pape R,Kissmehl R,Glas-Albrecht R,Plattner H
    BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.
    背景与目标: : 由于尚无关于抗微管剂对纤毛原生动物的影响的系统研究,因此我们筛选了各种此类化合物对草履虫四重草细胞培养物生长的影响。测试的化合物包括化学成分广泛不同的试剂,据报道对细胞类型广泛不同的影响。我们可以区分不同的药物作用 :( a) 鱼藤酮是唯一没有任何可识别作用的药物,(b) 与较高的动物细胞相比,另一组化合物 (包括秋水仙碱) 需要非常高的浓度,即相当接近细胞毒性水平; 该组还包括小管 (出乎意料的是,顺式和反式立体异构体之间没有任何区别)。(c) 第三组药物抑制细胞培养物的生长,而没有任何致死作用 (苯并咪唑,诺考达唑,帕苯达唑; [抗] 真菌抗生素灰黄霉素; 除草剂,氟拉林)。(d) 最后,一组试剂在植物 (除草剂,APM) 或高等动物细胞 (包括微管稳定剂,紫杉醇) 或两者 (长春碱,长春新碱,三乙基铅) 的浓度范围内具有活性,尽管它们在较高浓度下具有细胞毒性 (如 [b] 组的化合物)。因此,特别是可以进一步考虑 (c) 组和 (d) 组的化合物,以更详细地分析草履虫细胞中可能真正的抗微管作用。特别令人感兴趣的可能是诺考达唑,帕苯达唑和三氟拉林,因为它们可以在相对较低的浓度 (与其他细胞类型相当) 下抑制细胞培养物生长 (测试超过24小时),而不会损害细胞活力。
  • 【在计划生育环境中容易插入宫内避孕器。】 复制标题 收藏 收藏
    DOI:10.1111/ajo.12007 复制DOI
    作者列表:Harvey C,Bateson D,Wattimena J,Black KI
    BACKGROUND & AIMS: BACKGROUND:Intrauterine devices (IUDs) provide highly effective contraception for women worldwide. Reluctance to insert IUDs in the primary care setting may relate to concern about potential difficulty and complications, particularly in nulliparous women. AIMS:To determine the practitioner, patient and procedural factors associated with abandoned IUD insertion, practitioner-reported difficulty of insertion and adverse events during IUD insertions in the family planning setting. METHODS:This was a prospective study over a 12-month period of consecutive IUD insertions in four family planning clinics across New South Wales and Queensland. Patient, practitioner and device-related factors associated with abandoned IUD insertion, practitioner-reported ease of insertion and immediate insertion-related adverse events were analysed using logistic regression. RESULTS:Of 996 insertion procedures, successful insertion occurred in 95%, and 90% were reported as easy by the inserting doctor, including 80% of those in nulliparous women. Patient characteristics associated with an abandoned insertion were nulliparity (AOR 5.19; 2.49-10.82) or caesarean section-only deliveries (AOR 5.38; 2.58-11.22) and with practitioner-reported difficult insertion, nulliparity alone (AOR 1.98; 1.11-3.54). Practitioners inserting fewer than 100 IUDs over the 12-month study period more frequently rated insertions as difficult (AOR 1.76; 1.08-2.88). Complications occurred in 34 women and were more likely in nulliparous women (AOR 4.51; 2.16-9.39). CONCLUSIONS:Most IUDs can be successfully inserted, even in nulliparous women, in a primary care setting. Referral to a specialist may be appropriate for some women who are nulliparous or had caesarean section-only deliveries, depending on the experience of the practitioner.
    背景与目标:
  • 【丙型肝炎病毒的抗病毒耐药和直接作用抗病毒药物。】 复制标题 收藏 收藏
    DOI:10.3851/IMP2426 复制DOI
    作者列表:Aloia AL,Locarnini S,Beard MR
    BACKGROUND & AIMS: :Direct-acting antiviral (DAA) agents specifically target viral proteins. Two DAAs have been already been approved for the treatment of HCV infection and many more are in development. DAA treatment of HCV infection, however, leads to the selection of viral variants (produced by the error-prone HCV polymerase) that are resistant to the DAA agent in use. The selection of DAA-resistant HCV variants has been studied extensively in vitro and in vivo. Common amino acid substitution sites in each of the non-structural proteins are associated with DAA-resistance: D168, A155, A156 and V36 in NS3 protease; L31 and Y93 in NS5A; S282, S96, P495, M423, M414 and C316 in NS5B. In this review we cover the basic principles of DAA resistance, summarise the available resistance data for the various classes of DAAs and discuss the potential of DAA combination therapy for overcoming DAA-resistance, resulting in major advances in the treatment of HCV.
    背景与目标: : 直接作用抗病毒 (DAA) 药物专门针对病毒蛋白。已经批准了两种daa用于治疗HCV感染,并且还有更多的daa正在开发中。但是,对HCV感染的DAA治疗导致选择对使用中的DAA试剂具有抗性的病毒变体 (由易错的HCV聚合酶产生)。抗DAA HCV变体的选择已在体外和体内进行了广泛研究。每个非结构蛋白中常见的氨基酸取代位点与DAA抗性相关: NS3蛋白酶中的D168,A155,A156和V36; NS5A中的L31和Y93; NS5B中的S282,S96,P495,M423,M414和C316。在这篇综述中,我们涵盖了DAA耐药的基本原理,总结了各类DAA的可用耐药数据,并讨论了DAA联合疗法克服DAA耐药的潜力,从而在HCV治疗方面取得了重大进展。
  • 【肌动蛋白破坏剂对人类胚胎干细胞接触指导的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.biomaterials.2007.05.027 复制DOI
    作者列表:Gerecht S,Bettinger CJ,Zhang Z,Borenstein JT,Vunjak-Novakovic G,Langer R
    BACKGROUND & AIMS: :Mammalian cells respond to their substrates by complex changes in gene expression profiles, morphology, proliferation and migration. We report that substrate nanotopography alters morpohology and proliferation of human embryonic stem cells (hESCs). Fibronectin-coated poly(di-methyl siloxane) substrates with line-grating (600nm ridges with 600nm spacing and 600+/-150nm feature height) induced hESC alignment and elongation, mediated the organization of cytoskeletal components including actin, vimentin, and alpha-tubulin, and reduced proliferation. Spatial polarization of gamma-tubulin complexes was also observed in response to nanotopography. Furthermore, the addition of actin disrupting agents attenuated the alignment and proliferative effects of nanotopography. These findings further demonstrate the importance of interplay between cytoskeleton and substrate interactions as a key modulator of morphological and proliferative cellular response in hESCs on nanotopography.
    背景与目标: : 哺乳动物细胞通过基因表达谱,形态,增殖和迁移的复杂变化来响应其底物。我们报告了底物纳米照相改变了人类胚胎干细胞 (hESCs) 的形态和增殖。具有线光栅 (600nm脊具有600nm间距和600 +/-150nm特征高度) 的纤连蛋白包被的聚 (二-甲基硅氧烷) 基底诱导hESC排列和伸长,介导包括肌动蛋白、波形蛋白和 α-微管蛋白在内的细胞骨架组分的组织,并降低增殖。响应纳米照相,还观察到 γ-微管蛋白复合物的空间极化。此外,肌动蛋白破坏剂的加入减弱了纳米照相的排列和增殖作用。这些发现进一步证明了细胞骨架与底物相互作用之间的相互作用作为纳米照相hESCs中形态和增殖细胞反应的关键调节剂的重要性。
  • 【氯化和氟化7-氮杂苯地异喹啉的设计和合成,作为抑制拓扑异构酶I的有效细胞毒性抗癌剂。】 复制标题 收藏 收藏
    DOI:10.1021/acs.jmedchem.6b01870 复制DOI
    作者列表:Elsayed MSA,Su Y,Wang P,Sethi T,Agama K,Ravji A,Redon CE,Kiselev E,Horzmann KA,Freeman JL,Pommier Y,Cushman M
    BACKGROUND & AIMS: :The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.
    背景与目标: : 7-氮杂苯并异喹啉是细胞毒性拓扑异构酶I (Top1) 抑制剂。以前报道的代表带有3-硝基。本报告记录了用3-氯和3-氟取代基取代潜在的遗传毒性3-硝基,从而在人类癌细胞培养物中产生具有高Top1抑制活性和有效细胞毒性的化合物,并降低了动物模型中的致死率。一些新的Top1抑制剂对酪氨酸-DNA磷酸二酯酶1 (TDP1) 和酪氨酸-DNA磷酸二酯酶2 (TDP2) 也具有中等抑制活性,这两种酶参与了由Top1抑制剂产生的DNA损伤修复,并且它们在癌细胞中产生的DNA损伤明显多于正常细胞。18个新化合物的细胞毒性平均图中点 (MGM) GI50值在亚微摩尔 (0.033-0.630微米) 范围内。化合物16b和17b在MGM GI50值分别为0.063和0.033的人癌细胞培养物中是最有效的。通过分子建模研究了与Top1和tdp1的可能结合模式。
  • 【对人结肠癌细胞和神经细胞的苏拉明衍生物的双重筛选提供了具有降低毒性的新治疗剂。】 复制标题 收藏 收藏
    DOI:10.1016/0304-3835(91)90116-y 复制DOI
    作者列表:Baghdiguian S,Nickel P,Fantini J
    BACKGROUND & AIMS: :Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.
    背景与目标: : 苏拉明是目前用于抗肿瘤活性评估的聚阴离子化合物。在临床试验中遇到的主要问题之一是不良的神经毒性作用,可能是由于对神经细胞的直接细胞毒性作用所致。苏拉明还已知会触发人结肠癌细胞的分化,但长期治疗会导致溶酶体贮积障碍。这项研究的目的是评估苏拉明类似物的作用 :( i) 对人结肠癌细胞克隆HT29-D4的溶酶体系统; (ii) 对C6神经胶质瘤细胞的生长和形态。测试的衍生物之一NF036诱导了HT29-D4细胞的终末分化,而溶酶体系统没有任何损伤。此外,与苏拉明相反,NF036没有改变C6细胞的生长和形态。我们得出的结论是,苏拉明衍生物在人结肠癌细胞中诱导溶酶体贮积障碍的能力与其神经毒性作用之间存在关系。苏拉明类似物在HT29-D4和C6细胞上的双重筛选使我们能够鉴定一种新的候选抗肿瘤药物: nf036。
  • 【二苯甲酮衍生物作为抗疟药的QSAR分析。】 复制标题 收藏 收藏
    DOI:10.4103/0250-474X.102542 复制DOI
    作者列表:Mahajan S,Kamath V,Nayak S,Vaidya S
    BACKGROUND & AIMS: :A set of benzophenone derivatives was evaluated for the antimalarial activity against Plasmodium berghei in mice and the mean survival time of mice for all the compounds was determined. The QSAR analysis was carried out for the fourteen benzophenone derivatives using different physicochemical descriptors. The multiple linear regression analysis was used to correlate the physicochemical descriptors with the antimalarial activity of the benzophenone derivatives from the training set and the best QSAR model was developed, which was further used to predict the antimalarial activity of other compounds from the class of benzophenones. To confirm the predictivity of the best QSAR model, a new set (test set) of six compounds was designed, synthesized and evaluated for the antimalarial activity. A good correlation between the experimental and predicted antimalarial activities was obtained for the test set compounds in the validation procedure, indicating the high predictivity of the developed QSAR model. Five benzophenone derivatives, which showed good antimalarial activity, were further studied for their drug-likeliness characteristic and per cent oral absorption using software "QikProp". It was observed that all the five benzophenone derivatives were found to be good drug candidates and showed good oral absorption.
    背景与目标: : 评估了一组二苯甲酮衍生物对小鼠体内伯氏疟原虫的抗疟活性,并确定了所有化合物的小鼠平均存活时间。使用不同的物理化学描述符对14种二苯甲酮衍生物进行了QSAR分析。使用多元线性回归分析将物理化学描述符与训练集中的二苯甲酮衍生物的抗疟活性相关联,并开发了最佳QSAR模型,该模型进一步用于预测二苯甲酮类其他化合物的抗疟活性。为了确认最佳QSAR模型的预测性,设计,合成了一组新的六种化合物 (测试集),并评估了其抗疟活性。在验证程序中,测试集化合物的实验活性与预测的抗疟活性之间具有良好的相关性,表明已开发的QSAR模型具有很高的预测性。使用软件 “QikProp” 进一步研究了五种具有良好抗疟活性的二苯甲酮衍生物的药物似然特性和口服吸收百分率。观察到所有五种二苯甲酮衍生物均被发现是良好的候选药物,并显示出良好的口服吸收。
  • 【在11个国家/地区咨询后,影响妇女选择联合激素避孕方法的因素: CHOICE研究的子分析结果。】 复制标题 收藏 收藏
    DOI:10.3109/13625187.2013.819077 复制DOI
    作者列表:Bitzer J,Cupanik V,Fait T,Gemzell-Danielsson K,Grob P,Oddens BJ,Pawelczyk L,Unzeitig V
    BACKGROUND & AIMS: OBJECTIVES:To investigate which characteristics of women and healthcare professionals (HCPs) were associated with changing to another combined hormonal contraceptive (CHC) method after contraceptive counselling. METHODS:CHOICE was a cross-sectional survey in which 18,787 women were counselled about combined hormonal contraceptives, during which their contraceptive methods preferred both prior to and after counselling were recorded. In this subanalysis, characteristics associated with changing the method after counselling were determined using logistic regression models. RESULTS:The probability of intending to change from the pill to another method was associated with being older; university-educated; being in a steady relationship; a prior unintended pregnancy; a younger HCP or one who recommended methods other than the pill. Changing to the patch was associated with a female HCP or a HCP who recommended the patch or an injectable. Changing to the ring was associated with being over 21 years; university-educated; being in a relationship; previous hormonal method use; and counselling by a female HCP, a HCP < 60 years old, or a HCP who recommended the ring or an implant. The country of residence influenced these changes in a complex pattern. CONCLUSIONS:Women's choice of CHC methods after contraceptive counselling are influenced by their age, educational background, relationship status, prior unplanned pregnancies and country of residence, as well as age, gender and preferences of their HCP.
    背景与目标:
  • 【作为多功能剂的小檗碱-噻吩杂化物的合成和生物学评价: 抑制乙酰胆碱酯酶,丁酰胆碱酯酶,a β 聚集和抗氧化活性。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2013.07.011 复制DOI
    作者列表:Su T,Xie S,Wei H,Yan J,Huang L,Li X
    BACKGROUND & AIMS: :A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.
    背景与目标: : 设计,合成和评估了一系列小檗碱-噻吩杂化物,作为乙酰胆碱酯酶 (AChE),丁酰胆碱酯酶 (BuChE) 和 β-淀粉样蛋白 (A β) 聚集的抑制剂和抗氧化剂。在这些杂化物中,观察到化合物4f和4i,通过2-碳间隔物与o-甲基噻吩和o-氯噻吩连接的小檗碱是AChE的有效抑制剂,IC50值分别为0.077和0.042。在测试的化合物中,4i也是最有效的BuChE抑制剂,IC50值为0.662微米。AChE抑制剂复合物的动力学研究和分子建模模拟表明,这些小檗碱衍生物存在混合竞争结合模式。生物学研究还表明,这些杂种表现出有趣的活性,包括a β 聚集抑制和抗氧化特性。
  • 【克罗恩病患者术前使用抗TNF-α 药物和术后并发症的风险-一项全国性队列研究。】 复制标题 收藏 收藏
    DOI:10.1111/apt.12159 复制DOI
    作者列表:Nørgård BM,Nielsen J,Qvist N,Gradel KO,de Muckadell OB,Kjeldsen J
    BACKGROUND & AIMS: BACKGROUND:A possible negative role of pre-operative use of antitumour necrosis factor-alpha (anti-TNF-α) agents on post-operative outcomes in Crohn's disease (CD) patients is still debated. AIM:To examine the impact of pre-operative anti-TNF-α agents on post-operative outcomes 30 and 60 days after CD surgery in a nationwide Danish cohort. Outcomes were death, reoperation, anastomosis leakage, intra-abdominal abscess and bacteraemia. METHODS:We identified all patients having surgical procedures from 1 January 2000 to 31 December 2010 (n = 2293). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery (exposed) or not (unexposed). Outcomes were obtained from nationwide registries and a bacteraemia registry. Sub-analyses were performed for bacteraemia and for impact of pre-operative timing of anti-TNF-α agents. RESULTS:Among surgical procedures for CD, 214 were exposed and 2079 were not. We found no increased relative risks of death or abscess drainage 30 or 60 days after follow-up. Among exposed, 7.5% had a reoperation within 30 days vs. 8.6% among unexposed, adjusted odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.52-1.63. Among exposed, 3.8% had an anastomosis leakage within 30 days after surgery vs. 2.8% among unexposed, adjusted OR = 1.33, 95% CI: 0.59-3.02. No further cases of anastomosis leakages appeared within 60 days. Sub-analyses indicated no increased risk of bacteraemia after 30 days and no increased risks when anti-TNF-α agents were given ≤14 days before surgery. CONCLUSION:We found no significantly increased relative risks of post-operative complications after use of anti-TNF-α agents either 12 weeks or ≤14 days before surgery for Crohn's disease.
    背景与目标:
  • 【没有嵌合体作为阿尔茨海默氏病的治疗剂。】 复制标题 收藏 收藏
    DOI:10.2174/156720506777632925 复制DOI
    作者列表:Thatcher GR,Bennett BM,Reynolds JN
    BACKGROUND & AIMS: :NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.
    背景与目标: : NO是大脑中重要的信使分子,在学习和记忆中起着重要作用,尤其是通过ERK/CREB信号通路。NO也是神经保护剂; 已经证明了多种机制可以促进细胞存活,因为随着衰老,抗氧化剂和营养因子的水平降低。模拟NO生物活性的小分子,包括NO供体,可以改善认知并提供神经保护。有几条证据表明,阿尔茨海默氏病的神经变性和痴呆特征与 β-淀粉样蛋白在alpha7-nicotinic乙酰胆碱受体上的作用有关。Abeta与通过ERK信号级联起作用的alpha7-nicotinic ACh受体的相互作用将影响突触可塑性和记忆的途径中的淀粉样蛋白级联反应和胆碱能假说联系起来。这种相互作用还提供了与AD中NO/cGMP信号传导中断的联系,此外,最近发现的直接证据表明Abeta下调了NO/cGMP/CREB途径。可溶性鸟苷酸环化酶的激活升高了大脑中的cGMP,代表了治疗AD和其他神经退行性疾病的治疗方法的核心要素,此外,有证据表明NO可能显示出不依赖cGMP的活性,并且可以通过多种生化信号传导途径起作用,以确保承受压力的神经元的存活。GT 1061是一种NO嵌合体,一种NO模拟化合物,包含辅助的,协同药效团,目前正在阿尔茨海默氏症的临床试验中。没有嵌合体和杂合硝酸盐有望作为具有多个作用位点的AD的治疗方法。
  • 【用抗感染剂治疗的中心静脉导管在预防血流感染方面的临床有效性和成本效益: 系统评价和经济评价。】 复制标题 收藏 收藏
    DOI:10.3310/hta12120 复制DOI
    作者列表:Hockenhull JC,Dwan K,Boland A,Smith G,Bagust A,Dündar Y,Gamble C,McLeod C,Walley T,Dickson R
    BACKGROUND & AIMS: OBJECTIVES:To assess the clinical effectiveness and cost-effectiveness of central venous catheters (CVCs) treated with anti-infective agents in preventing catheter-related bloodstream infection (CRBSI). DATA SOURCES:Major electronic databases were searched from 1985 to August 2005. REVIEW METHODS:The systematic clinical and economic reviews were conducted according to accepted procedures. Only full economic evaluations (synthesis of costs and benefits) comparing the use of anti-infective central venous catheters (AI-CVCs) with untreated CVCs or other treated catheters were selected for inclusion in the economic review. RESULTS:A total of 32 trials met the clinical inclusion criteria. Seven different types of AI-CVC were identified, with the most frequently tested being chlorhexidine and silver sulfadiazine (CHSS) (externally treated), CHSS (externally and internally treated) and minocycline rifampicin (internally and externally treated). In general, the trials were of a poor quality in terms of reported methodology, microbiological relevance and control of confounding variables. The pooled result suggests a statistically significant advantage for AI-CVCs in comparison to standard catheters in reducing CRBSI [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.34 to 0.60, 24 studies, I-squared = 0%, fixed effects]. Analysis by subgroups of catheters demonstrates that antibiotic-treated catheters and catheters treated internally and externally decrease CRBSI rates significantly (OR 0.26, 95% CI 0.15 to 0.46, six studies, I-squared = 0%, fixed effects, and OR 0.43, 95% CI 0.26 to 0.70, nine studies, I-squared = 0%, fixed effects, respectively). Catheters treated only externally demonstrate a wider CI and non-significant effect (OR 0.67, 95% CI 0.43 to 1.06, nine studies, I-squared = 0%, fixed effects). A treatment effect was also found for trials with an average duration of between 5 and 12 days, and for the one study with a mean duration of over 20 days. There was a statistically significant treatment effect for both femoral and jugular insertion sites and for those studies reporting a mix of insertion sites. The treatment effect was not observed in trials using exclusively subclavian insertion sites. Of the four trials that compared treated catheters, one reported a benefit of antibiotic-treated catheters over catheters treated externally with CHSS. All three sensitivity analyses testing for study design differences reported a statistically significant treatment effect. The review was limited owing to the quality of the trials included, marked differences in the definitions and methods of diagnosis of CRBSI, and inconsistent reporting of risk factors and patient population factors. Furthermore, two-thirds of trials were commercially funded. The economic performance (cost-effectiveness and potential cost-savings) of using AI-CVCs to reduce the number of CRBSIs in patients requiring a CVC was also reviewed. Results show that the use of AI-CVCs instead of standard CVCs can lead to a reduction in CRBSIs and decreased medical costs. To complement the reviews, a basic decision-analytic model was constructed to explore a range of possible scenarios for the NHS in England and Wales. Results show that for every patient who receives an AI-CVC there is an estimated cost-saving of 138.20 pounds. The multivariate sensitivity analyses estimate potentially large cost-savings, depending on the size of the population, under a wide range of cost and clinical assumptions. However, those considering the purchase of AI-CVCs should ensure that their patient populations and the important characteristics of local clinical practice are indeed similar to those described in this economic evaluation. CONCLUSIONS:Overall, AI-CVCs are clinically effective and relatively inexpensive and therefore their integration into clinical practice can be justified. However, the use of these anti-infective catheters without the appropriate use of other practical care initiatives will have only a limited success on the prevention of CRBSIs. Comparative trials are required to determine which, if any, of the treated catheters is the most effective. Pragmatic research related to the effectiveness of bundles of care that may reduce rates of CRBSI is also warranted.
    背景与目标:
  • 【女性健康倡议中雌激素加孕激素的随机试验中的激素治疗和乳腺癌风险。】 复制标题 收藏 收藏
    DOI:10.1016/j.maturitas.2006.05.004 复制DOI
    作者列表:Anderson GL,Chlebowski RT,Rossouw JE,Rodabough RJ,McTiernan A,Margolis KL,Aggerwal A,David Curb J,Hendrix SL,Allan Hubbell F,Khandekar J,Lane DS,Lasser N,Lopez AM,Potter J,Ritenbaugh C
    BACKGROUND & AIMS: OBJECTIVES:To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial. METHODS:Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up. RESULTS:Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors. CONCLUSION:A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.
    背景与目标:

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