完全随机设计与配伍组设计效率的比较

完全随机设计与配伍组设计效率的比较毛宗福陈华罗毅平＊＊（湖北医科大学医学统计教研室武汉４３００７１）完全随机设计属非均衡随机对照试验设计。配合组设计亦称随机区组设计，属均衡随机对照试验设计。本文视试验设计及相应的方差分析为一体，对二者的研究效率、优...     

靶向临床试验不同设计方法的统计学性能比较

目的:本文拟对三种常用的靶向临床试验设计方法进行统计学性能模拟研究,为进行靶向临床试验提供设计选择依据.方法:在全随机设计、富集设计、策略设计三种常用的靶向临床试验设计方法下,设定不同的参数条件,借助模拟方法探讨其在同等参数条件下样本量与把握度之间的关系,并依此对比各设计方法的统计学性能.结果:在随机分配两组样本含量相同的条件下,富集设计总能获得最大的把握度.除了在靶向治疗药物对无靶点病人产生负影响的情况下,全随机设计都可以获得比策略设计更大的把握度.当试验药物除了对靶点阳性病人有效,如果对靶点阴性病人也有一定疗效时,在相同把握度情况下,富集设计为筛选合格病人所需的样本量会大于全随机设计.结论:如果靶向治疗药物对无靶点病人也有疗效,或者目前尚没有很好的靶点诊断方法并且病人中靶点阳性率较高,我们建议首选可进行亚组分析的全随机设计.     

疾病亚型分配不等的多中心临床试验随机化方案及SAS程序

介绍多种疾病亚型、各中心分配例数不等的临床试验随机化方案的设计.设计规程包括随机化参数设定、随机化规定、SAS随机程序设计,以及由此产生的随机数字、疾病亚型和试验中心随机编码、试验病例随机编码、处理组的随机编码及试验药物包装表.     

益气养阴法治疗慢性肾炎的Meta分析

目的 利用循证医学系统评价方法评价中医益气养阴法治疗慢性肾炎的疗效及安全性.方法 检索国内外各种医学期刊杂志,选择中医益气养阴法治疗慢性肾炎与单纯西医治疗慢性肾炎的随机对照的试验研究.共纳入9篇随机/半随机对照临床试验并进行Meta分析.结果 与西药治疗组相比,益气养阴法在治疗慢性肾炎总体疗效,降低血尿素氮(BUN)、血肌酐(SCr)等方面优于纯西医治疗组.结论 益气养阴法治疗慢性肾炎的疗效优于纯西医治疗,但还需要设计良好的随机对照及多中心临床试验做进一步证实.     

盐酸特比萘芬片在中国健康受试者体内的生物等效性研究

目的 研究盐酸特比萘芬片在中国健康受试者中的药代动力学,评价国产受试制剂与原研参比制剂的生物等效性.方法 采用空腹/餐后、随机、开放、单剂量、两周期、两序列、双交叉试验设计.空腹试验和餐后试验各入组36例健康受试者,随机分为2组,每周期单次空腹或餐后口服盐酸特比萘芬片受试制剂或参比制剂125 mg.用液相色谱-串联质谱...     

正交试验设计的误差与效率及其分析方法的探讨

本文以方差分析的观点探讨正交试验设计的实践与理论问题,及试验误差与效率问题。作者运用试验实践数据资料,在相同的试验规模下,分析不同设计方案的误差与效率,并与随机区组类设计比较以评价不同方案的优、劣,并对正交试验上的某些存在向题总结出八点改进意见。     

注射剂I期耐受性临床试验方案设计要点

为完善注射剂I期耐受性临床试验各环节的技术要求,从用药剂量、递增方案、疗程、配液的选择、给药方法、随机入组设计、理化结果的判断、人体反应预测等方面总结归纳,提出标准操作步骤。经试验证实能有效保证试验质量。     

丙泊酚对异氟烷镇痛、催眠效应的影响

目的 观察丙泊酚对异氟烷镇痛、催眠效应的影响.方法 试验小鼠120只(雌雄比2:1)随机分为热板法试验组(n=40,雌性)、甩尾法试验组(n=40,雌雄各半)和催眠试验法组(n=40,雌雄各半),各组再按分层随机设计分为NS组(生理盐水组)、Pp组(丙泊酚组)、Iso组(异氟烷组)和Pp+Iso组(丙泊酚与异氟烷合用组...     

栅栏取骨与大块取骨的临床比较

目的 对栅栏取骨与大块取骨两种方法进行临床比较.方法 前瞻性分析2010年6月-2011年6月该院行各种手术需取自体髂骨的患者60例,随机分成栅栏取骨组和大块取骨组,比较两组患者供骨区顽固疼痛、麻木、感染、髂骨凹陷、髂骨骨折、局部血肿、取骨区疝等术后并发症.结果 两组在麻木并发症方面无统计学意义,而髂骨凹陷、髂骨骨折、供骨区顽固疼痛、局部血肿、取骨区疝、感染等并发症,栅栏取骨组明显低于大块取骨组.结论 栅栏取骨通过重建髂骨三皮质取骨区的骨缺损,术后并发症少,较大块取骨优势明显,值得临床推广应用.     

羟丁酸钠与恩氟烷合用对小鼠镇痛催眠作用的影响

目的 观察羟丁酸钠对恩氟烷镇痛、催眠作用的影响.方法 120只受试小鼠随机分为热板法试验组(n=40,均为雌性)、扭体法试验组(n=40,雌雄各半)及催眠试验组(n=40,雌雄各半).各组再按分层随机区组设计分为生理盐水组(NS组)、羟丁酸钠组(SO组)、恩氟烷组(En组)和羟丁酸钠与恩氟烷合用组(SO+En组),观察...     

用Excel软件进行药物毒理实验的随机分组

目的：借助Excel软件进行随机化分组。方法：利用Excel软件插入随机数字和排序的功能设计随机分组表。结果：采用本法可方便、迅速地将动物以随机数的顺序分配到各处理组中。结论：用Excel软件进行随机化分组简单、快速、准确和方便。     

Polymer design and incorporation methods for polymeric micelle carrier system containing water-insoluble anti-cancer agent camptothecin

A water-insoluble anti-cancer agent, camptothecin (CPT) was incorporated to a polymeric micelle carrier system forming from poly(ethylene glycol)-poly(aspartate) block copolymers. Incorporation efficiency and stability were analyzed in correlation with chemical structures of the inner core-forming hydrophobic blocks as well as with incorporation methods. Among three incorporation methods (dialysis, emulsion and evaporation methods), an evaporation method brought about much higher CPT yields with less aggregation than the other two methods. By the evaporation method, CPT was incorporated to polymeric micelles in considerably high yields and with high stability using block copolymers possessing high contents of benzyl and methylnaphtyl ester groups as hydrophobic moieties. This indicates importance of molecular design of the hydrophobic block chain to obtain targeting using polymeric micelle carriers as well as importance of the drug incorporation method.     

Smart and genetically engineered biomaterials and drug delivery systems.

The design, synthesis, and properties of novel stimuli-sensitive and genetically engineered biomaterials and drug delivery systems are reviewed. Two approaches to their engineering are presented. One approach is to improve the traditional methods of synthesis, as demonstrated by the example of controlled copolymerization of alpha-amino acid N-carboxyanhydrides. The other approach, discussed in more detail, uses genetic engineering methods. The design of hybrid hydrogel systems whose components derive from at least two distinct classes of molecules, e.g., synthetic macromolecules and protein domains, is assessed. The design of self-assembling block copolymers is discussed in detail. Finally, the pharmaceutics related applications of these materials are presented.     

Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes

It has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. We assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). Terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not induce it at all. Thus, the chronic atrioventricular block cynomolgus monkeys can be used for studying drug interaction-associated torsade de pointes, providing a non-clinical strategy to circumvent untoward drug interactions in patients specially under polypharmacy.     

Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs

Block of human ether-a-go-go related gene (hERG) K(+) channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to potentially fatal arrhythmias. This undesirable long QT side effect has been a major reason for the withdrawal of medications from the pharmaceutical market. Understanding the molecular basis of hERG block is therefore essential to facilitate the design of safe drugs. Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625). We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions. Although changing the basic nitrogen from quaternary to tertiary accelerated the onset of block, the IC(50) and kinetics for recovery from block were similar. In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block. The highest potency was achieved with polar or electronegative para-substituents, whereas neutral para-substituents had potencies more than 100-fold lower. Results from mutagenesis and molecular modeling studies suggest that phenyl ring para-substituents influence drug interactions with Thr-623, Ser-624, and Tyr-652 and strongly affect binding affinity. Together, these findings suggest that modifying the para-substituent could be a useful strategy for reducing hERG potency and increasing the safety margin of compounds in development.     

Design of small molecule libraries for NMR screening and other applications in drug discovery

There are conceptual differences between high-throughput screening (HTS) and fragment-based screening by NMR. The number of compounds in libraries for NMR screening may be significantly smaller than those used for HTS. Because one relies on a small library its design is significantly important and is the object of this article. A short introduction on fragment-based NMR screening approaches will be provided. Although there are currently very few reports describing the design of libraries of small molecules for NMR screening, aspects of the question of how to compile diverse collections of small molecular fragments useful for drug design were previously addressed for the purposes of combinatorial library design and de novo drug design. As these disciplines are highly interrelated and are applied in an interconnected manner with NMR screening within the drug discovery process, a review of combinatorial library design and especially the building block or fragment selection strategies applied for combinatorial library design and de novo design is well suited to reveal fundamental strategies and potential techniques for the design of NMR screening libraries. This section will be rounded off by a report on hands-on-experience with the design of the Novartis second-site NMR screening library and practical considerations for the design of compound mixtures. Rather than providing an exact protocol general guidelines will be indicated.     

Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding

A 96-well equilibrium dialysis block was designed and constructed that is compatible with most standard 96-well format laboratory supplies and instruments. The unique design of the dialysis apparatus allows one to dispense and aspirate from either or both the sample and dialysate sides from the top of the apparatus, which is not possible with systems currently on the market. This feature permits the investigator to analyze a large number of samples, time points, or replicates in the same experiment. The novel alignment of the dialysis membrane vertically in the well maximizes the surface-to-volume ratio, eliminates problems associated with trapped air pockets, and allows one to add or remove samples independently or all at once. Furthermore, the design of the apparatus allows both the sample and dialysate sides of the dialysis well to be accessible by robotic systems, so assays can be readily automated. Teflon construction is used to minimize nonspecific binding of test samples to the apparatus. The device is reusable, easily assembled, and can be shaken in controlled temperature environments to decrease the time required to reach equilibrium as well as facilitate dissolution of test compounds. Plasma protein binding values obtained for 10 diverse compounds using standard dialysis equipment and the 96-well dialysis block validates this method.     

阴式子宫切除改良术的临床应用

为了提高阴式子宫切除术的手术效果，简化手术步骤，缩短手术时间，减少术中出血和术后并发症、我们对61例有手术适应证的患者随机分为两组，分别施行了阴式子宫切除的传统式和改良式的手术。结果证实，阴式子宫切除的改良术与传统术式比较，具有以上诸多优点。是一种安全易行，效果良好，便于推广应用的手术方法。     

均匀设计法筛选茵陈蒿汤抗脂肪肝脂质代谢异常的效应组分

目的:运用均匀设计法筛选茵陈蒿汤抗脂肪肝脂质代谢紊乱的效应组分及其最优剂量配比,探讨揭示复方配伍理论科学内涵的研究方法。方法:将茵陈蒿汤(茵陈、栀子、大黄)进行分组设计,分为6种中药组合,对高脂饮食诱导的大鼠脂肪肝模型进行干预,观察各组大鼠肝脏的病理变化,并以血清三酰甘油(TG)、肝组织TG、血清低密度脂蛋白(LDL)测定作为筛选指标,分析不同作用途径的效应组分及其最优剂量配比。结果:较之正常组,模型组血清TG、LDL和肝组织TG含量均明显升高(P<0.05~0.01),肝组织存在明显脂肪变性;各药物组上述脂肪病理改变程度均明显减轻。根据均匀设计实验逐步回归分析,降低血清TG和降低肝组织TG的效应组分分别是茵陈、栀子。而茵陈与大黄对降低血清LDL有明显疗效,以茵陈0.3g+大黄0.15g为最优剂量组合。结论:茵陈蒿汤通过多途径调节脂肪肝的脂质代谢,其不同作用途径存在特定的效应组分及相应的最优剂量配比。