BACKGROUND & AIMS: :New hydrazone derivatives were synthesized via the nucleophilic addition-elimination reaction of 2-[(1-methyl-1H-tetrazol-5-yl)thio)]acetohydrazide with aromatic aldehydes/ketones. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Genotoxicity of the most effective anticandidal compounds was evaluated by umuC and Ames assays. All compounds were also investigated for their cytotoxic effects on NIH3T3 and A549 cell lines. Compound 8 was the most effective antifungal derivative against C. albicans (ATCC-90028) with a MIC value of 0.05 mg/mL. Compound 5 can be identified as the most promising anticancer agent against A549 cancer cell lines due to its inhibitory effect on A549 cell lines and low toxicity to NIH3T3 cells.

背景与目标： ：通过2-[（（1-甲基-1H-四唑-5-基）硫基）]乙酰肼与芳香族醛/酮的亲核加成消除反应合成了新的衍生物。该化合物在体外针对各种念珠菌进行了测试，并与酮康唑进行了比较。通过umuC和Ames分析评估了最有效的抗候选化合物的基因毒性。还研究了所有化合物对NIH3T3和A549细胞系的细胞毒性作用。化合物8是针对白色念珠菌的最有效的抗真菌衍生物（ATCC-90028），MIC值为0.05 mg / mL。化合物5由于其对A549细胞系的抑制作用和对NIH3T3细胞的低毒性而可以被确定为最有前途的针对A549癌细胞系的抗癌剂。

BACKGROUND & AIMS: :Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.

背景与目标： 烯基硼酸已显示出重要的生物活性，可促进神经保护作用。我们已经确定了它们对β-淀粉样蛋白（βA）聚集过程，β-分泌酶和乙酰胆碱酯酶活性对无细胞系统，氧化还原和脂质过氧化状态的影响，以及对APPswe神经母细胞瘤细胞株凋亡死亡的脆弱性的影响，过氧化氢处理前后。我们已经发现2-芳基乙烯基硼酸及其某些酯具有一系列特性，这使得它们非常有用地用作影响涉及AD的多个生物学靶标的神经保护剂。这些性能是相关的2-芳基硼酸无法比拟的。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： ：设计，合成和评估了一系列新型白藜芦醇衍生物，作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，（E）-5-（4-（异丙基氨基）苯乙烯基）苯-1,3-二醇表现出强力的β-淀粉样蛋白聚集抑制活性，这可通过ThT荧光测定法证实（71.65％在20μM）和透射电子显微镜（TEM）。化合物7-1也表现出良好的抗氧化活性（在氧自由基吸收能力测定中为4.12 Trolox当量，并且在10μM下细胞中的活性氧减少了37％）。化合物7f，7i，7j和7l的细胞毒性分析表明，在60μM浓度下，这些化合物的毒性低于白藜芦醇。

BACKGROUND & AIMS: :In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

背景与目标： ：在这项研究中，我们评估了新型八氢吡嗪[2,1-a：5,4-a']二异喹啉衍生物（1-7）在MCF-7和MDA-MB-231乳腺癌细胞中的细胞毒活性和抗增殖能力线。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。在与被测化合物孵育24小时后，测定了胱天蛋白酶3、8、9和10的活性，以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行比较。我们的研究表明，在两种分析过的乳腺癌细胞系中，活性最高的化合物是化合物3和4。我们还观察到所有化合物均可诱导细胞凋亡。我们证明了胱天蛋白酶3，8，9和10较高的活动，这证实凋亡的诱导与外部和内部细胞死亡途径相关。我们的研究表明，通过激活外在和内在的凋亡途径，二异喹啉衍生物类中的新化合物有望成为抗癌治疗的候选药物。

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： 近年来，与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中存在的顺式烯烃的合适模拟物的认识，我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现，在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物，C2位上的部分影响抗增殖活性，效力顺序为NHCH（3）> Me> N（CH（3））（2） 。相对于C 2-氨基对应物，N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N，N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b，3d和3e是最有效的化合物作为抗增殖剂，其IC（50）值从低微摩尔到一位数纳摩尔，此外，它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。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不会引起线粒体去极化。

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定作用的植物提取物。植物心理药物是德国最常用的草药之一。某些制剂的功效和无害性已通过高质量的临床试验确定。 1975年至1992年间，共发表了34项临床研究，涉及2326例患者，研究了银杏特殊提取物EGb 761和LI 1370的作用。迄今为止，已对圣约翰草的酒精提取物进行了2120位患者的28项临床试验。卡瓦和缬草提取物的治疗功效已分别在六项和四项对照研究中进行了研究。通常，可能有很高的安慰剂作用，这就是为什么必须在这些研究中包括对照组的原因。相对于合成的心理药物而言，一个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准则进行了大规模的测试程序。对于其他植物心理药物，由于现在要求的标准过高，存在无法进行进一步临床试验的危险。

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虫原虫影响的系统研究，因此我们筛选了多种此类化合物对草履虫草履虫细胞培养物生长的影响。测试的化合物包括化学成分差异很大的试剂，并且据报道对多种细胞类型具有影响。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）需要很高的浓度，即接近细胞毒性水平；该组还包括微管唑（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）第三类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，苯达达唑； [抗]真菌抗生素，灰黄霉素；除草剂三氟拉林）。 （d）最后，一组试剂在植物（除草剂，APM）或高级动物细胞（包括微管稳定剂，紫杉醇）或两者（长春碱，长春新碱，三乙基铅）的浓度范围内均具有活性。它们在较高浓度下具有细胞毒性（如[b]组化合物）。因此，对于草履虫细胞中可能真正的抗微管作用的更详细的分析，可以进一步考虑组（c）以及可能的组（d）的化合物。 Nocodazole，parbendazole和trifluralin特别令人感兴趣，因为它们可以在相对低的浓度下（与其他细胞类型相比）抑制细胞培养物的生长（经过24小时测试），而不会损害细胞的活力。

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）剂专门针对病毒蛋白。已经批准了两种DAA用于治疗HCV感染，并且还有更多的药物正在开发中。但是，DAA对HCV感染的治疗导致选择对使用中的DAA剂具有抗性的病毒变体（由易出错的HCV聚合酶产生）。在体外和体内已经广泛研究了抗DAA的HCV变异体的选择。每种非结构蛋白中的常见氨基酸取代位点均与DAA耐药性相关：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。在本综述中，我们涵盖了DAA耐药性的基本原理，总结了各种DAA耐药性的可用耐药性数据，并讨论了DAA联合疗法克服DAA耐药性的潜力，从而在HCV的治疗方面取得了重大进展。

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。我们报告说，基底纳米形貌改变了人类胚胎干细胞（hESCs）的形态和增殖。纤连蛋白涂层的聚二甲基硅氧烷底物具有线栅（间距为600nm，间距为600nm，特征高度为600 / -150nm），诱导hESC对准和伸长，介导包括肌动蛋白，波形蛋白和α-微管蛋白的细胞骨架成分的组织，并减少扩散。响应纳米形貌还观察到了γ-微管蛋白复合物的空间极化。此外，肌动蛋白破坏剂的添加减弱了纳米形貌的排列和增殖作用。这些发现进一步证明了细胞骨架和底物相互作用之间相互作用的重要性，这是纳米地形图上hESCs中形态学和增殖细胞应答的关键调节剂。

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-氮杂茚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一个3-硝基基团。本报告记录了潜在的具有遗传毒性的3-硝基被3-氯和3-氟取代基取代，从而导致在人类癌细胞培养中具有高Top1抑制活性和强细胞毒性的化合物，并降低了动物模型的致死率。一些新的Top1抑制剂还具有对酪氨酰DNA磷酸二酯酶1（TDP1）和酪氨酰DNA磷酸二酯酶2（TDP2）的中等抑制活性，这两种酶都参与了由Top1抑制剂引起的DNA损伤修复，并且它们产生的DNA明显更多。在癌细胞中的损伤要比正常细胞中的损伤大。 18种新化合物的细胞毒性平均图中点（MGM）GI50值在亚微摩尔（0.033-0.630μM）范围内。化合物16b和17b在人类癌细胞培养物中最有效，其MGM GI50值分别为0.063和0.033μM。通过分子建模研究了与Top1和TDP1可能的结合模式。

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： ：Suramin是目前正在评估抗肿瘤活性的聚阴离子化合物。临床试验期间遇到的主要问题之一是不良的神经毒性作用，这可能是由于对神经细胞的直接细胞毒性作用所致。还已知苏拉明会触发人结肠癌细胞的分化，但是长期治疗会引起溶酶体贮积症。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）C6胶质瘤细胞的生长和形态。测试的一种衍生物NF036诱导了HT29-D4细胞的终末分化，而对溶酶体系统没有任何损害。此外，与苏拉明相反，NF036不会改变C6细胞的生长和形态。我们得出结论，苏拉明衍生物在人结肠癌细胞中诱导溶酶体贮积病的能力与其神经毒性作用之间存在关联。在HT29-D4和C6细胞上对苏拉明类似物的双重筛选使我们能够鉴定出新的候选抗肿瘤药：NF036。

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。使用不同的理化指标对十四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指标与训练集中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模型的可预测性，设计，合成了一套新的（测试集）六种化合物，并评估了其抗疟活性。在验证过程中，测试化合物的实验和预测的抗疟活性之间具有良好的相关性，表明所开发的QSAR模型具有很高的预测性。使用软件“ QikProp”进一步研究了五种显示出良好抗疟活性的二苯甲酮衍生物的类药物特性和口服吸收百分比。观察到所有五种二苯甲酮衍生物均被认为是良好的候选药物，并表现出良好的口服吸收性。

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，合成并评估了一系列小ber碱-硫代苯基杂化物，作为乙酰胆碱酯酶（AChE），丁酰胆碱酯酶（BuChE）和β-淀粉样蛋白（Aβ）聚集的抑制剂和抗氧化剂。在这些杂种中，观察到化合物4f和4i（通过2碳间隔基与邻甲基硫代苯基和邻氯硫代苯基连接的小ber碱）是有效的AChE抑制剂，IC50值分别为0.077和0.042μM。在测试的化合物中，4i也是BuChE的最强抑制剂，IC50值为0.662μM。 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，包括抑制Aβ聚集和抗氧化性能。

BACKGROUND & AIMS: :The effect of ketamine on myocardial contractile force was examined in rabbit papillary muscles in order to determine the underlying mechanism of action of the anesthetic. Ketamine HCl (20 and 40 mg/L) inhibited rested-state contractions that are dependent on the transsarcolemmal influx of Ca2+ for activation and reduced the upstroke velocity of the slow action potential, which reflects Ca2+ influx through the slow Ca2+ channel. On the other hand, ketamine had a relatively small effect on potentiated-state contractions and no effect on rapid cooling induced contractures, both of which are activated by the release of Ca2+ stored in the sarcoplasmic reticulum. These results suggest that ketamine inhibition of transsarcolemmal Ca2+ influx plays a major role in the negative inotropic action of the anesthetic.

背景与目标： ：检查氯胺酮对兔乳头肌中心肌收缩力的作用，以确定麻醉剂的潜在作用机理。盐酸氯胺酮（20和40 mg / L）抑制了静息状态的收缩，而静息状态的收缩依赖于Ca2的跨膜层流入激活，并降低了慢动作电位的上冲程速度，这反映了Ca2通过缓慢的Ca2通道流入。另一方面，氯胺酮对增强状态的收缩影响相对较小，而对快速冷却引起的挛缩没有影响，两者均通过肌浆网中储存的Ca2释放而被激活。这些结果表明氯胺酮抑制跨肌膜Ca2内流在麻醉剂的负性肌力作用中起主要作用。

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： 背景：在克罗恩病（CD）患者中，术前使用抗肿瘤坏死因子-α（anti-TNF-α）药物对术后结局的可能负面作用仍在争论中。
目的：探讨丹麦全国队列CD手术后30和60天的术前抗TNF-α药物对术后结局的影响。结果是死亡，再次手术，吻合口漏，腹腔内脓肿和菌血症。
方法：我们确定了从2000年1月1日至2010年12月31日（n = 2293）的所有接受外科手术治疗的患者。根据手术前（未暴露）或未手术（未暴露）前12周内使用抗TNF-α药物对患者进行分类。结果是从全国性注册机构和菌血症注册机构获得的。对菌血症和抗TNF-α药物的术前时机的影响进行了亚分析。
结果：在CD的外科手术中，有214例暴露，而2079例则没有。随访后30或60天，我们没有发现死亡或脓肿引流的相对风险增加。在暴露的患者中，有7.5％在30天内进行了再次手术，而未暴露的，调整后的优势比（OR）= 0.92,95％的置信区间（CI）：0.52-1.63为8.6％。在暴露的人群中，有3.8％的患者在术后30天内发生了吻合口漏，而在未暴露的，调整后的OR = 1.33、95％CI：0.59-3.02的患者中，则为2.8％。在60天内没有其他病例发生吻合口漏。子分析表明，术后30天内细菌菌血症的风险没有增加，并且在手术前≤14天给予抗TNF-α药物的风险也没有增加。
结论：我们发现克罗恩病患者在手术前12周或≤14天使用抗TNF-α药物后，术后并发症的相对风险没有显着增加。