The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines

BACKGROUND: A number of recent studies have identified interleukin (IL)-6 as an important regulator of prostate cancer growth. Here, we investigate the potential interaction of IL-6 with phosphatidylinositol (PI)-3 kinase, a key growth regulatory enzyme, in prostate cancer cell lines. METHODS: Tyrosine phosphorylation of p85, the regulatory subunit of PI-3 kinase, in the human prostate cancer cell lines LNCaP and PC-3 was assessed by sequential immunoprecipitation with anti-p85 antibody and immunoblotting with anti-phosphotyrosine. The effects of wortmannin, an inhibitor of PI-3 kinase, and/or IL-6 on cell growth were assessed by MTT assays. DNA laddering experiments were performed to assay for programmed cell death. RESULTS: Tyrosine phosphorylation of p85 is upregulated by IL-6 in both LNCaP and PC-3. IL-6 promotes coprecipitation of p85 with gp130, the signal-transducing component of the IL-6 receptor. Inhibition of PI-3 kinase with wortmannin induces programmed cell death in PC-3 cells. In contrast, wortmannin has no effect on LNCaP growth when used alone; however, combined with IL-6, wortmannin promotes apoptosis in these cells. CONCLUSIONS: PI-3 kinase is involved in IL-6 signal transduction and delivers an antiapoptotic signal in human prostate cancer cell lines.     

恶性肿瘤中TGF-β1信号传递分子DPC4/Smad4的研究进展

DPC4/Smad4基因是新近被鉴定的一个肿瘤抑制基因 ,其编码的DPC4/Smad4蛋白是TGF β信号传导通路中的重要传导蛋白 ,是TGF β配体、受体结合后后续信号传导的胞质递质 ,参与TGF β受体激活后的信号传导。DPC4/Smad4调控的下游目的基因有p2 1WAF1、uPA、PAI 1、VEGF、TSP 1。转化生长因子 -β(transforminggrowthfactorbeta ,TGF β)信号传导通路的配体、受体、胞内信号传导分子Smad蛋白及其调控的下游目的基因等组成一个肿瘤生长的负性调节 ,通路中任何一个元件的异常都可引起信号传导紊乱 ,导致肿瘤发生     

儿童功能性消化不良与幽门螺杆菌感染的关系

目的探讨儿童功能性消化不良与幽门螺杆菌（HP）感染的关系。方法用ELISA法和胃液尿素酶试验检测163例功能性消化不良和54例健康儿童的HP感染情况。结果血清HP-IgG阳性申功能性消化不良组高于对照组（43．6％:14.8％，X2＝14．7，ｐ＜0.01），尿素酶试验阳性率功能性消化不良组也高于对照组（15．3％:3．7％，x2＝5．07，p＜o．05）。内镜检查15例患儿中，慢性胃炎12例（占80％）。经抗HP治疗功能性消化不良症状消失。结论儿童功能性消化不良与HP感染相关，HP是该疾病的主要病因之一。     

耳穴疗法治疗老人失眠症之临床研究

目的:尝试利用科学性之方法探讨耳穴磁疗对老人失眠症之效果.方法:120位60岁或以上之老年患者,随机分配入三组.第一组及第二组为对照组,分别贴有灯芯或王不留行籽(不加压);第三组为实验组,贴有每粒含66高斯之磁珠(不加压).为针对老年患者常见之脏腑功能衰弱而致失眠,各人均选取相同之穴位:神门、心、肾、肝、脾、皮质下及枕,疗程共3周.结果:疗程完毕后,使用磁珠作耳疗之实验组于治疗前后的睡眠效果指数有明显之改进(P＜0.05),显效17%,有效为65%,总有效率为82%.此外,利用多元回归之反向淘汱法分析女性参加者之数据,发现利用磁珠作耳疗及参加者年龄对预测睡眠效果指数达显著水准(F3,106=9.04,P＜0.001,R2=0.20).结论:耳穴磁疗能有效地改善老人失眠症.     

Different astroglial reaction between the vagal dorsal motor nucleus and nucleus ambiguus following vagal-hypoglossal nerve anastomosis in cats

The dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA) were both traced with horseradish peroxidase (HRP) retrograde labelling technique after vagal-hypoglossal nerve anastomosis (VHA). By light microscopy, reinnervation of the new target, viz. tongue skeletal musculature, by DMV and NA was established at 22 days postoperation (dpo) as shown by the neuronal labelling with HRP. Ultrastructurally, signs of retrograde degeneration occurred in some DMV and NA neurons between 3 and 25 days after VHA. The incidence of darkened dendrites, an early sign of dendritic loss, was more common in the DMV compared to the NA. Accompanying the neuronal alteration were drastic astrocytic reactions in the DMV, but not in the NA. Between 3 and 7 dpo, the astrocytes in the DMV showed extensively hypertrophied processes and by 22 dpo, the somata and dendrites of HRP-labelled DMV neurons, but not NA's, appeared to be delineated by the increased lamellar astrocytic processes. Such a feature was sustained throughout the remaining postoperative intervals up to 500 dpo. It is concluded that the DMV motoneurons being autonomic in nature are probably not conducive to the newly acquired target organ. Hence, the insulation of the regenerating DMV motoneurons by the astroglial ensheathment would be vital in the neuronal remodelling and reconstruction of the vagal-hypoglossal pathway.     

Inducible nitric oxide synthase expression elicited in the mouse brain by inflammatory mediators circulating in the cerebrospinal fluid

Expression of inducible nitric oxide synthase (iNOS) protein was studied in the brain after intracerebroventricular injections of interferon (IFN)-gamma, and IFN-gamma combined with lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha, compared to ovalbumin as control. Wild-type mice and mice with targeted deletion of the IFN-gamma receptor gene were used. Findings based on iNOS immunoreactivity were evaluated at 1, 2, 4 and 7 days post-injection, using also quantitative image analysis and double labeling with glial cell markers. IFN-gamma administration induced iNOS immmunostaining in activated microglia and macrophages in the parenchyma surrounding the ventricular system, several cortical fields and fiber tracts. IFN-gamma-elicited iNOS immunoreactivity was down-regulated after 1 day. The number of iNOS-immunopositive cells was significantly enhanced by co-administration of LPS or TNF-alpha; IFN-gamma+TNF-alpha injections also resulted in longer persistence of iNOS immunoreactivity. No immunopositive cells were seen in the brain of IFN-gamma receptor knockout mice after IFN-gamma administration; very few immunostained macrophages were detected in these cases, mostly around the injection needle track, after co-administration of LPS or TNF-alpha. Western blot analysis confirmed a marked iNOS induction in the brain of wild-type mice 24 h after IFN-gamma+LPS injections. The findings show that inflammatory mediators circulating in the cerebrospinal fluid induce in vivo iNOS in the brain with topographical selectivity and temporal regulation. The data also demonstrate that the signaling cascade activated by IFN-gamma binding to its receptor is critical for iNOS induction, and the synergistic action of LPS and TNF-alpha as iNOS inducers in brain cells is largely mediated by the receptor-regulated action of IFN-gamma.     

上海市闵行区中小学生肥胖患病率调查

[目的 ]　了解上海市闵行区中小学生肥胖和超重患病率情况 ,为预防儿童肥胖制订防制策略及措施提供基础资料。　 [方法 ]　普查区内共 40 3 10名中小学学生的身高体重。采用体重指数 (BMI)和身高别体重法同时评价调查对象的肥胖患病率。　 [结果 ]　研究人群平均年龄 ( 12 .5 9± 3 .0 7)岁 ,总体BMI为 18.63± 3 .3 1,其中男性BMI高于女性。以BMI法为评价标准总体肥胖患病率为 2 .76%,超重患病率为 11.5 7%;以身高别体重法为参考标准则肥胖的患病率为 6.17%,超重的患病率为 6.76%,两种评价方法的总体患病率差异有极显著性。肥胖和超重患病率总体上呈现男高女低 ,并随年龄增加而逐渐减低。　 [结论 ]　闵行区中小学生的肥胖总体患病率呈现随年龄的增高而逐渐降低趋势。中小学生超重比例较高 ,应及早制订防制策略及措施 ,减少肥胖发生