患者招募

缓慢的患者招募工作是新药物研发延迟的主要原因。人们曾相继提议过许多解决方案用于提高患者招募速度和减缓延迟现象。最有效的解决方案就是临床试验的全球化，药物临床试验质量管理规范（GCP）运动也推动了该全球化的进程。根据美国食品及药物管理局（FDA）章程在世界范围内进行的调查，呈现出的是一幅安全可靠的画面。几乎所有调查员报告的都是遵守了GCP规范。不遵守的只是例外，只占了检查数量的不到5％。     

保持生产力

新分子研究和新药物开发正变得越来越困难，成本也越来越高。虽然全世界的医药行业研发的开支从1999年到2003年增加了36％，但是同期开发的新分子药物数量却下降了很多。     

脑波促使运动神经元生长

美国威斯康星大学麦迪逊分校研究人员首次通过人类胚胎干细胞培养出了脊髓运动神经元。这一进步使得研究人员可以为神经系统活动筛选新药物建立运动神经元模型系统。     

国际咨询团

Patrjck Couvreur教授是法国巴黎国家科学研究中心理事。他在巴黎南部大学领导研究中心，致力于开发纳米药物及新型给药系统。他同时也参与到了Medjtech的建立中。Meditech是巴黎的一家的公众与私人研究团体，致力于新型医药制品与生物技术疗法。他说：“大规模筛选不能替代药物开发的想象科学。”     

保肝解毒颗粒对雷公藤多苷致急性肝损伤小鼠自由基脂质过氧化反应的影响

目的探讨保肝解毒颗粒对雷公藤多苷致急性肝损伤小鼠自由基脂质过氧化反应的影响。方法60只小鼠随机分为模型组、保肝解毒颗粒大、中、小剂量组、甘利欣对照组和空白对照组,分别以相应剂量药物灌胃5 d,再以雷公藤多苷灌胃造模,检测小鼠血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px)水平。结果模型组血清SOD、GSH-Px水平明显降低,MDA水平明显升高;保肝解毒颗粒各剂量组均可有效降低血清ALT、AST和MDA水平,显著提高GSH-Px水平,大剂量组尚可显著提高血清SOD水平,与模型组比较差异均有统计学意义(P<0.05)。结论保肝解毒颗粒具有明显的降酶保肝作用和抗自由基脂质过氧化作用。     

短发卡RNA抑制survivin表达并诱导CNE-2细胞凋亡

目的观察以短发卡RNA(shRNA)抑制鼻咽癌细胞survivin表达对细胞凋亡与增殖的影响。方法构建特异性survivin shRNA,转染CNE-2细胞。分组:A组为空白对照组;B组为阴性干扰组,转染pSIREN-survivin/nonsenseshRNA;C组为阳性干扰24h组,转染pSIREN-survivin/shRNA;D组为阳性干扰48h组,转染pSIREN-survivin/shRNA。以RT-PCR、Western-blot分别测定细胞survivin mRNA及蛋白,PI、TUNEL及MTT检测细胞周期、凋亡率、细胞增殖。结果转染效率约(70.90±4.76)%;C组survivin mRNA和蛋白抑制率分别为(41.58±0.63)%、(68.29±0.52)%;D组抑制率分别为(63.64±0.96)%、(70.83±0.48)%。C组凋亡率为(36.24±0.78)%,D组为(50.37±0.85)%,显著高于B组和A组;S期细胞减少,G2/M期比例增高;MTT结果提示细胞增殖受到明显抑制。结论特异性shRNA可有效干扰CNE-2内survivin的表达,诱导细胞凋亡并抑制其过度增殖。     

热休克蛋白70反义寡核苷酸联合化疗药物抑制肝癌细胞HepG2增殖的实验研究

目的研究热休克蛋白70反义寡核苷酸(HSP70ASODN)联合化疗药物对肝癌细胞的增殖抑制作用。方法采用MTT法比较转染组和未转染组联合化疗药物在肝癌细胞增殖方面的差异。结果检测HepG2细胞株对化疗药物5-氟尿嘧啶(5-Fu)的敏感性,24、48、72、96h未转染组与转染组的细胞生长抑制率分别为:0.323±0.043、0.468±0.015,0.394±0.045、0.663±0.026,0.526±0.021、0.793±0.041,0.616±0.016、0.899±0.044(P均<0.05)。检测HepG2细胞株对化疗药物ADM的敏感性,24、48、72、96h未转染组与转染组的细胞生长抑制率分别为:0.157±0.021、0.421±0.037,0.394±0.045、0.574±0.037,0.293±0.036、0.637±0.019,0.302±0.023、0.658±0.038(P均<0.05)。结论 HSP70ASODN能增强化疗药物对HepG2的增殖抑制作用;HSP70ASODN联合多药化疗优于联合单药化疗。     

Effect of acidity of drugs on the prediction of human oral absorption by biopartitioning micellar chromatography

Biopartitioning micellar chromatography (BMC) is a potentially high throughput and low cost alternative for in vitro prediction of drug absorption, which can mimic the drug partitioning process in biological systems. In this paper, a data set of 56 compounds representing acidic, basic, neutral and amphoteric drugs from various structure classes with human oral absorption (HOA) data available were employed to show the effect of acidity of drugs in oral absorption prediction. HOA was reciprocally correlated to the negative value of the capacity factor (kBMC) determined by BMC at pH 7.4 and 6.5. The relationships between kBMC and the corresponding HOA values of all compounds were rather poor, but the correlations were improved when the acidity of drugs was taken into consideration. Moreover, the proposed models allowed obtaining of good predictive values for both highly and poorly absorbed compounds. It is demonstrated that the constructed models derived from compounds with the same kind of charge property are of more practically meaningful and rigorous.     

Preliminary study on Salvia miltiorrhiza bung endophytic fungus

Objective To select the strains which can produce tanshinone ⅡA like its host plant Salvia miltiorrhiza bung. Methods A total of 50 strains of endophytic fungi were isolated from healthy, living and symptomless tissues of Salvia miltiorrhiza bung, among which 29 strains were obtained from the root, 14 from the stem, 3 from the leaf, 3 from the flower and 1 from the seed. Their antimicrobial activities against nine different bacteria, including both Gram-negative and Gram-positive bacteria, were measured by Oxford plate agar diffusion bioassay. Results Our data showed that all but four strains had significant antibacterial activities on at least one indicator bacterium to some extent, and five strains (DR1, DR4, DR16, DR18 and DF2) manifested quite prominent antibacterial activities against certain pathogenic bacteria. In some degree, it might indicate that this endophytic fungus isolated from the tissues of Salvia miltiorrhiza bung has a potential value as a natural antibacterial medicine as well. Thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) were carried out to test selected strains, both inside and outside of the cell to see if any strain can produce tanshinone ⅡA. The result showed that extracts from three strains, labeled as DR12 (outside cell), DR21 (inside cell) and DF3 (inside cell), had a component with the same Rf value in TLC assay as that of authentic tanshinone ⅡA. The extract from DR12 (outside cell) and DR21 (inside cell) had a peak at retention time identical to that of authentic tanshinone ⅡA in HPLC. Conclusion The fungi appear to produce the bioactive compound tanshinone ⅡA, and they could be used to produce tanshinone ⅡA by fermentation. It provides a new way to synthesize this natural medicine.     

5-氨基乙酰丙酸光动力疗法对人卵巢癌细胞的杀伤作用

目的 探讨5-氨基乙酰丙酸(5-aminolevulinic acid,5-ALA)介导的光动力疗法(photodynamic therapy,PDT)对体外培养的人卵巢癌3AO细胞的杀伤效应.方法 显微镜观察细胞形态;MTT法检测5-ALA介导的PDT(5-ALA-PDT)对3AO细胞增殖的抑制作用;PI染色及Annexin V-PI双染结合流式细胞术分析5-ALA-PDT对3AO细胞的细胞周期及死亡方式的影响.结果 5-ALA-PDT后3AO细胞出现典型的凋亡形态学改变;细胞抑制率随着5-ALA浓度及激光能量密度的升高而升高(P<0.01),当光敏剂浓度达到一定水平时,抑制率不再相应升高,该作用存在浓度饱和现象;流式细胞术显示PDT后细胞发生了G0/G1期生长停顿(P<0.05),有明显的晚期凋亡和继发性坏死(P<0.01).结论 5-ALA对卵巢癌3AO细胞有杀伤作用;凋亡是5-ALA-PDT杀伤卵巢癌细胞的一种机制.