新药临床试验的原理与操作（6）：—统计学处理的标准操作规程指南（续1）

介绍制药业统计学家协会标准操作规程指南的第5－8部分。强调必须仔细设计随机化编码表的产生、分发和破盲 的程序,同时应核查是否已遵循了所制定的随机化。数据管理要有详细计划,特别是数据库设计、管理和维护的程序和责任人,期中分析必须事先计划,要尽可能避免期中分析对试验的影响。最后讲座了统计报告的撰写和应包含的内容。     

新药生物统计指导原则（草案）

1、1设计方案新药研究必须根据“重复、对照、随机、均衡”的原则，事先制定研究方案，临床研究方案应经伦理委员会批准，实施中如需变更，应经批准，并在总结报告中反映变更情况和理由，基础研究也应有实验设计方案备查。1.2可比性分析对于处理前的各组数据必须进行可比性分析。临床研究中，可用病例情况分析进行统计对比。基础研究中，应以用药前数据进行组间显性检验，如在统计学上不拒绝各组来自同一总体(P>0．05)，可认为可比性合格。1．3检测数据新药申报资料．必须提供详细数据．应写出检测方法及数据单位，数据应至少有3位有效数字，标准差至少有2位有效数字。应避免不必要的数据转换，如需转换，应说明理由。数据缺失更要说明详细原因。     

新药临床试验的原理与操作（6）

介绍了制药业统计学家协会的标准操作规程指南中有关随机化与盲法、数据管理、期中分析和统计报告的情况)；详细讨论了为保证数据质量和结论的科学性而必须遵循的统计学原则；强调既要最大限度地坚持盲法，同时又要保证可以紧急解盲，数据管理的每一步都必须有章可循，统计分析必须注意可能出现的偏性，还列出了统计报告的主要内容。     

新型（生）隐球菌脑膜炎的诊断与治疗（附30例报告）

报告了经确诊的新型（生）隐球菌脑膜炎３０例的临床诊断与治疗情况，并对部分病例误诊原因作了初步分析。由于本病易误诊为结脑，颅内占位性病变并颅高压综合征，病毒性脑炎等，故为避免误诊，除应详细了解病史及发病特征外，还应进行病原学检查。ＣＳＦ涂片墨汁染色找隐球菌，操作简单迅速，检出率高，不失为早期确诊的方法。霉菌培养因时间长，不宜人微言轻早期诊断方法。二性霉素Ｂ仍为目前治疗隐球菌脑膜炎的有效药物。但应注意     

对（FDA）包含软件医疗设备上市前提交资料的研究

目的研究性分析FDA要求的包含软件产品的医疗设备上市前需要提交的资料。方法介绍了如何确认软件设备关注度和每种关注度需要提交的文档内容。结果与结论关注度文件应包括设备设计阐述、设计实施文件、软件测试说明、软件管理风险与危害分析及连接设计、实施、测试和风险管理的可追溯性分析。     

中国南海总合草苔虫抗癌活性成分研究（IV）Bryostatin 8,16的分离与结构鉴定

以体外抗癌活性为指标,采用多种层析分离技术,从采自广东大鹏湾海域的总合草苔中追踪分离得到8个活性单体。利用电喷雾离子质谱（ESI－MS）和高分辨（600MHz)核磁共振二 维谱技术测定活性化合成物的结构,分别鉴定为：bryostatin4,bryostatin5,bryostatin6,bryostatin8,bryostatin10,bryostatin11,bryostatin16,brytostatin18。其中,bryostatin8(I)和bryostatin16(Ⅱ）是首次从南海总合草苔虫中获得,并在体外表现出显著的抗癌活性。     

确保上市医疗器械的安全性：器械和放射健康中心（CDRH）医疗器械上市后安全性监测计划（五）

确保上市后医疗器械的安全性是各国监督管理部门应履行的职责。医疗器械在设计、功能方面的复杂性及风险特征决定了其监管方法的特异性。美国食品药品监督管理局下属的器械和放射健康中心（CDRH）负责医疗器械的上市前审批和上市后监管。相应地，CDRH通过上市前审批计划和上市后监测计划，使得医疗器械从设计、上市使用，到更新换代，组成了一个维护公众健康安全的统一体。本文为CDRH医疗器械上市后安全性监测计划的全部译文，包括CDRH上市后安全性监测框架及所包含的内容，以及用来监测和评估与使用医疗器械有关的不良事件和风险的方法，并提出持续性改进措施。希望能为加强我国医疗器械监管，建立规范化、系统化的监管模式提供借鉴。     

确保上市医疗器械的安全性：器械和放射健康中心（CDRH）医疗器械上市后安全性监测计划（三）

确保上市后医疗器械的安全性是各国监督管理部门应履行的职责。医疗器械在设计、功能方面的复杂性及风险特征决定了其监管方法的特异性。美国食品药品监督管理局下属的器械和放射健康中心（CDRH）负责医疗器械的上市前审批和上市后监管。相应地，CDRH通过上市前审批计划和上市后监测计划，使得医疗器械从设计、上市使用，到更新换代，组成了一个维护公众健康安全的统一体。本文为CDRH医疗器械上市后安全性监测计划的全部译文，包括CDRH上市后安全性监测框架及所包含的内容，以及用来监测和评估与使用医疗器械有关的不良事件和风险的方法，并提出持续性改进措施。希望能为加强我国医疗器械监管，建立规范化、系统化的监管模式提供借鉴。     

总合散光的横切面的研究

本对5～74岁散光患3745例(6954只眼)的总合散光进行了横切面的研究和分析现报告如下。     

后房型人工晶体植入术（三）

术前估计后房型人工晶体植入手术的术前估计同标准的白内障摘除术。由于现代手术技术进步和允许病人术后早期活动，病人的全身情况一般能接受植入手术。不过，对虚弱老人手术时还是应警惕；对久病或恶性肿瘤病人不宜施行手术。术前首先是估计病人的一般情况，内容包括病人能否胜任手术；术中、术后可能出现哪些问题；晶体植入手术是否对病人有益，视力能改善程度，尤其当病人眼部有病理改变（如：黄斑疾病、视野缺损、青光眼、糖尿病眼底改变等）时，是否应当作手术？术前还要选择人工晶体和计算它的屈光力。术前必须仔细分析每个患者全身及…     

alpha-glucosidase (CHO) (Genzyme)

Genzyme General is developing recombinant human alpha-glucosidase, produced in mammalian cell culture, as a potential treatment for Pompe disease. By July 2004, enrollment was completed in two clinical trials and an observational study in adults. Genzyme was planning to file for regulatory approval in Europe during 2004, followed by filings in the US and Japan in mid-2005.     

(S)-oxybutynin (Sepracor)

Sepracor is developing (S)-oxybutynin, a single-isomer version of Alza's Ditropan (racemic oxybutynin), a muscarinic acetylcholine receptor antagonist, as a potential treatment for urinary incontinence.     

Allosteric interaction of zinc with recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) GABA(A) receptors

In a recent study we have provided evidence that inhibition of native GABA(A) receptors by zinc depends primarily on the allosteric modulation of receptor gating. Both the kinetics and the sensitivity of the GABA(A) receptor to zinc depend on subunit composition, especially on the presence of the gamma(2) subunit. To analyze the mechanism of action of zinc its effects have been tested on recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors expressed in HEK 293 cells. The currents produced by ultrafast application of GABA have been measured to assess the impact of zinc ions on GABA(A) receptor gating with resolution corresponding to the time scale of synaptic currents. While, as expected, zinc markedly reduced the peak amplitude of alpha(1)beta(2)-mediated currents, its effect on kinetics was significantly different from that observed for alpha(1)beta(2)gamma(2). In particular, unlike alpha(1)beta(2)gamma(2), zinc did not affect the onset of alpha(1)beta(2)-mediated responses. Moreover, zinc increased the extent of desensitisation of alpha(1)beta(2)gamma(2) receptors and reduced desensitisation of alpha(1)beta(2) ones. Quantitative analysis suggests that zinc exerts an allosteric modulation on both alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors. Zinc effects on alpha(1)beta(2)gamma(2) were qualitatively similar to those reported for native receptors.     

Di(isononyl) phthalate (DINP) and di(isodecyl) phthalate (DIDP) are not mutagenic

Recently there have been reports of liver and kidney tumors in rodents following long-term exposure to di(isononyl) phthalate (DINP). Mechanistic studies suggested that the liver tumors were a consequence of peroxisomal proliferation, whereas the kidney tumors (found only in male rats) were associated with induction of alpha(2u)-globulin. Because both peroxisomal proliferation and alpha(2u)-globulin are considered to be non-genotoxic carcinogenic processes, it seemed appropriate to investigate the genotoxic potential of DINP. Additional studies were also conducted on di(isodecyl) phthalate (DIDP), a structurally related substance that also induces peroxisomal proliferation, although it has not been tested in a carcinogenicity bioassay. The DINP was tested in Salmonella, in vitro cytogenetics and mouse micronucleus assays, whereas DIDP was evaluated in a mouse micronucleus test. All of these tests produced negative results, i.e. neither phthalate was mutagenic in any of the test systems. These data are consistent with results of other published and unpublished genotoxicity tests and provide support for the hypothesis that the liver and kidney tumors induced by DINP were the result of non-genotoxic processes.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

1,2-环己二胺柠檬酸铂(Ⅱ)及异柠檬酸铂(Ⅱ)的合成和抗癌活性

报道了1,2-环己二胺异柠檬酸铂(Ⅱ)及1,2-环己二胺柠檬酸铂(Ⅱ)的合成及鉴定方法。抗癌试验表明前者在40及80mg/kg 剂量下对小鼠 L1210、P388及S180均有明显的抑瘤作用,且有部分动物可治愈;后者对 L1210也有明显的抑瘤作用,但较前者为弱。     

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.     

4（R）—（6—氨基—9H—嘌呤—9—基）—2（R）—（羟甲基）四氢呋喃—3（R）—醇的合成

为寻找抗HIV化合物,我们以D－核糖为原料,经甲基化、硅烷基化、还原裂解反应制得重要中间体1－脱氧核糖（5）,再通过形成环状亚砜化合物,与NaN3发生反应后,经过还原、缩合、环合、氨化、脱保护基反应制得异脱氧腺嘌呤核苷（1）,各步反应收率均超过70％。其抗HIV活性测定尚在进行中。     

Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP)

The effect of TFMPP, an agonist of the 5-HT1b receptors, was studied in mice on several psychopharmacological parameters. In contrast to imipramine-like drugs, TFMPP neither antagonized reserpine-induced hypothermia nor increased yohimbine-induced toxicity. Similarly to imipramine-like drugs, TFMPP antagonized oxotremorine-induced hypothermia and was active in the behavioural despair test. In addition, TFMPP normalized a social behavioural deficit induced by isolation. The effects of TFMPP on oxotremorine-induced hypothermia in the behavioural despair test and in the isolation-induced social behavioural deficit are all antagonized by d-1 propranolol. It is concluded that TFMPP seems to possess psychotropic activity resembling only in part that of imipramine-like drugs and that these actions may be mediated through 5-HT1b receptors.