丹红注射液中迷迭香酸、紫草酸、丹酚酸B在大鼠血浆中的浓度测定

目的:建立测定大鼠血浆中丹红注射液中迷迭香酸、紫草酸、丹酚酸B浓度的方法。方法:采用HPLC法,色谱柱为Diamonsil C18柱(250 mm×4.6 mm5,μm);流动相为乙腈-0.4%的磷酸水,梯度洗脱;流速为1.0 mL.min-1;检测波长为288 nm。结果:迷迭香酸在4.0～100.0μg.mL-1浓度范围内线性关系良好(r=0.9925);回收率在85.0%～101.4%之间,日内、日间RSD<8%;紫草酸在4.0～100.0μg.mL-1浓度范围内线性关系良好(r=0.991 1);回收率在84.4%～93.9%之间,日内、日间RSD<9%;丹酚酸B在2.0～200.0μg.mL-1浓度范围内线性关系良好(r=0.998 6);回收率在80.0%～97.4%之间,日内、日间RSD<5%。结论:本文所建立的方法灵敏度好、准确率高,可用于丹红注射液中迷迭香酸、紫草酸、丹酚酸B的药代动力学研究。     

火焰原子吸收法测定维生素B12片中钴的含量

目的:建立火焰原子吸收法测定维生素B12片中钴的含量。方法:检测波长为240.7 nm,灯电流为4.0 mA,狭缝宽度为0.2 nm,燃气流量为2.0 L·min-1,助燃气流量为13.5 L·min-1。结果:钴浓度在0.01～0.20 mg·L-1范围内线性关系良好(r=0.9999),平均加样回收率为98.8%(n=9)。结论:该方法简单,结果准确,灵敏度高,可有效控制维生素B12片的质量。     

Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m²/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m²/day. The dose level of 80 mg/m²/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC₅₀ values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.     

A Portfolio-Based Approach to Optimize Proof-of-Concept Clinical Trials

Improving proof-of-concept (PoC) studies is a primary lever for improving drug development. Since drug development is often done by institutions that work on multiple drugs simultaneously, the present work focused on optimum choices for rates of false positive (α) and false negative (β) results across a portfolio of PoC studies. Simple examples and a newly derived equation provided conceptual understanding of basic principles regarding optimum choices of α and β in PoC trials. In examples that incorporated realistic development costs and constraints, the levels of α and β that maximized the number of approved drugs and portfolio value varied by scenario. Optimum choices were sensitive to the probability the drug was effective and to the proportion of total investment cost prior to establishing PoC. Results of the present investigation agree with previous research in that it is important to assess optimum levels of α and β. However, the present work also highlighted the need to consider cost structure using realistic input parameters relevant to the question of interest.     

金骨莲胶囊对炎症模型大鼠的抗炎作用及机制研究

目的:研究金骨莲胶囊对炎症模型大鼠的抗炎作用及机制.方法:将48只大鼠随机分为空白对照组、模型组、金骨莲胶囊低、中、高剂量组(0.66、1.32、2.64 g/kg)和地塞米松组(阳性对照,0.945 mg/kg),每组8只.空白对照组和模型组大鼠灌胃等体积水,其余各组大鼠灌胃相应药物,每天给药2次,连续3天.末次给药...     

前S1抗原、HBV DNA及HBeAg在乙型肝炎病毒检测中的临床意义

目的 了解乙型肝炎患者前S1抗原(Pre-S1)、HBV DNA及HBeAg的相关性,并评价它们在诊断HBV复制中的临床意义.方法 应用ELISA、荧光定量PCR法(FQ-PCR)对198例乙型肝炎患者进行Pre-S1、HBV DNA及HBV血清标志物五项(两对半)检测.结果 198例乙型肝炎患者中Pre-S1阳性107例(54.0%),HBV DNA阳性111例(56.1%),HBeAg阳性90例(45.5%),三者同时阳性72例(36.4%),Pre-S1与HBV DNA阳性率比较,差异无统计学意义(P>0.05).在90例HBeAg阳性样本中,Pre-S1阳性72例(80.0%),HBVDNA阳性74例(82.2%),三者具有较高的符合率.在108例HBeAg阴性样本中,Pre-S1阳性35例(32.4%),HBV DNA阳性37例(34.2%),Pre-S1与HBV DNA检出率比较,两者高度一致(χ2=0.08,P>0.05).结论 Pre-S1与HBV DNA能敏感反映HBV复制的情况,尤其可以协助诊断HBeAg阴性的乙型肝炎患者是否有HBV复制,对于判断患者的病情及指导治疗具有重要的临床意义.     

乙型肝炎病毒前S1抗原在核苷类药物抗病毒治疗上的意义

目的 研究HBV前S1抗原(Pre-S1)在指导核苷(酸)类药物抗病毒治疗上的意义.方法 将HBeAg阳性患者经拉米夫定治疗获得完全应答并维持疗效6个月以上停药者以Pre-S1是否阳性分成两组,比较两组的远期疗效.结果 Pre-S1阴性组一年、二年远期持续应答率分别为80%、21.05%,差异有统计学意义(P＜0.01).阳性组患者一年、二年远期持续应答率分别为65%、10.53%,差异有统计学意义(P＜0.01).结论 检测Pre-S1可作为判断慢性乙型肝炎患者经核苷(酸)类药物治疗完全应答后远期疗效和预后的重要指标.     

DNA芯片检测乙型肝炎病毒基因型

目的 制备检测HBV基因型的DNA芯片并进行杂交验证.方法 设计多条HBV分型寡核苷酸探针,固定于醛基基片的特定位置,制备成芯片,采用酶呈色技术(BCIP/NBT显色)检测杂交信号,进行杂交验证分析.结果 106例临床样本均测出基因型,其中B型37例,C型69例;对所有样本进行测序分析,结果与芯片杂交一致,杂交的灵敏度和重复性等指标均佳.结论 DNA芯片检测HBV基因型,操作简便易行,技术要求不高,适于临床推广应用.     

遗传易感因素与慢性乙型肝炎干扰素治疗反应的相关性

IFN-α以抗病毒及免疫调节双莺作用用于慢性乙型肝炎的治疗,对治疗反应的早期预测有利于治疗的持续.随着人类基因组学和蛋白质组学的研究进展,国内外对HBV感染发病及治疗反应遗传易感因素有较多报道,主要集中于抗病毒蛋白和免疫调节相关细胞因子的基因多态性.此文就遗传易感因素对IFN-α治疗慢性乙型肝炎疗效的影响作了综述.     

脑源性神经营养因子/酪氨酸激酶B受体信号参与不同水平伤害性感受的调制

脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)是神经营养因子家族的重要成员之一,BDNF支持了发育期间一些神经系统神经元的生长与生存.BDNF是成年突触可塑性的一种重要调质.外周炎症、神经离断、神经损伤及神经病理性疼痛模型在内的多种疼痛均能改变神经系统内BDNF的表达.BDNF通过与其高亲和力受体酪氨酸激酶B(re-ceptior tyrosine kinase,TrkB)受体结合,从而激活下游信号通路发挥效应,在不同水平伤害性信息的调制中发挥了重要作用.