新型强效免疫抑制剂F904的结构测定

分析吸水链霉菌 (Streptomyces hygroscopicus) FC90 4产生的具有免疫抑制活性的化合物 F90 4的理化性质及光谱学性质 (UV、IR、NMR、X- Ray衍射 ) ,证实化合物 F90 4的分子结构及空间构型与西罗莫司(sirolimus,又称 rapamycin)同质。     

缺氧诱导卵巢上皮性癌细胞形成拟态血管的前期研究

目的探讨缺氧在卵巢上皮性癌细胞系SKOV3和ES2细胞拟态血管形成过程中的作用及西罗莫司对其的抑制效应。方法建立人工基底膜基质凝胶Matrigel三维培养系统,分别在常氧(常氧组)、缺氧(缺氧组)、缺氧时加入西罗莫司(缺氧+西罗莫司组)等条件下诱导,观察SKOV3和ES2细胞形成拟态血管的能力;应用相差显微镜和扫描电镜观察拟态血管的形态及其立体结构的特点;用RT-PCR技术检测不同条件下缺氧诱导因子(HIF)1αmRNA的相对表达量。结果培养7d后,缺氧组SKOV3和ES2细胞出现变形、伸展,形成腔样、管状、分支和网络状等管道结构;而常氧组及缺氧+西罗莫司组,部分细胞出现伸展但不形成管道结构。缺氧组SKOV3和ES2细胞的HIF-1αmRNA表达量分别为0·801±0·034和0·736±0·059,显著高于缺氧+西罗莫司组(分别为0·025±0·007和0·231±0·035;P<0·01,P<0·05)和常氧组(分别为0·010±0·004和0·011±0·002;P均<0·01)。结论缺氧是卵巢上皮性癌细胞形成拟态血管的重要诱导因素,西罗莫司通过抑制HIF-1αmRNA的表达阻断拟态血管的形成。     

Renal transplantation: The present and the future

Children receiving kidney transplants in the modern era in developed countries have excellent overall results. Graft survival and patient survival in children is now virtually equal to that in adult organ recipients. Deceased donor source kidneys are no longer associated with significantly inferior outcomes. These advances are in large part due to development in more potent immunosuppressive agents and newer combinations. These advances have also come at a price in the form of increased post-transplant infections. The transplant community is now moving to minimization protocols to reduce the adverse effects of many of the medications and to reduce the incidence of infections. Newer techniques of diagnosis of acute rejection, degree of immunosuppression and DNA-based viral surveillance are changing the face of clinical practice. Newer technologies such as stem cell transplantation, tissue engineering and xenotransplantation promise even more changes in the future.     

比较两种药物涂层支架临床疗效的多中心注册研究

1 文献类型 治疗和预防。 2 证据水平 4。     

冠心病患者应用药物洗脱支架临床观察

目的 研究Excel药物洗脱支架治疗冠状动脉原发病变的临床疗效.方法 入选2004年9月2008年3月接受Excel药物洗脱支架治疗的冠心病患者692例.观察术后30 d和3、9及12个月主要心脏不良事件发生率,支架内再狭窄率和靶血管重建率.结果 与中国Cypher select注册研究比较,接受Excel支架治疗的患者和接受Cypher支架治疗的患者在术后12个月支架内再狭窄率(9.1%比9.6%,P>0.05)和主要心脏不良事件发生率(3.8%比6.5%,P>0.05)方面差异无统计学意义.结论 Excel西罗莫司洗脱支架和Cypher西罗莫司洗脱支架近期疗效相似.

Abstract：

Objective To study the effects of excel simlimus eluting stent on patients with coronary heart disease.Methods Totally 692 patients having excel stent therapy were enrolled in this study.Twelve months follow-up for major adverse cardiac events(MACE)rate,restenosis rate and target lesion revascularization rate was performed. Results Compared with Chinese Cypher Select Registry Study,patients having Excel stent therapy had no significant difference in 12 months restenosis rate(9.1%VS 9.6%,P>0.05)and 12 months MACE rate 13.8%vs 6.51%,P>0.05).Conclusion The efficacy and safety of excel sirolimus eluting stent is as good as Cypher eluting stent.     

免疫抑制剂F904的免疫抑制作用

新免疫抑制Ｆ９０４是吸水链老菌（ｓｔｒｅｐｔｏｍｙｃｅｓ ｈｙｇｒｏｓｃｏｐｉｃｕｓ）ＦＣ９０４产生的三烯大环内酯化合物,化学结构研究证实它与新型强效免疫抑制剂西罗莫司（ｓｉｒｏｌｉｍｕｓ,ｒａｐａｍｙｃｉｎ）同质。体外免疫学试验显示Ｆ９０４能抑制ＰＨＡ诱导的Ｔ淋巴细胞转化,抑制作用较环孢素（ＣｓＡ）强约１００倍,ＩＣ５０〈０．１ｎｍｏｌ／Ｌ;抑制ＣｏｎＡ诱导的Ｔ淋巴细胞转化,抑制作用同ＣｓＳ相当     

mTOR 抑制剂在乳腺癌内分泌及 HER-2靶向治疗耐药中的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）位于磷脂酰肌醇3激酶（PI3K）-蛋白激酶 B（Akt）细胞信号通路的下游,已有研究表明该通路的异常激活与乳腺癌的内分泌及抗人表皮生长因子受体-2（HER-2）的靶向治疗耐药相关。在既往传统药物的基础上通过联合 mTOR 抑制剂阻断该条通路的异常活化,在防止肿瘤细胞的耐药性发展及恢复初始敏感性方面均体现出了良好的应用前景,mTOR 抑制剂将有望成为乳腺癌治疗的新希望。     

肾移植术后患者全血西罗莫司浓度监测结果分析

目的:探讨肾移植术后患者全血西罗莫司浓度的治疗窗以及西罗莫司对血常规、肝肾功能、血脂和尿蛋白的影响。方法:采用微粒子发光免疫分析技术（MEIA）测全血西罗莫司谷浓度。对3年来294例次肾移植术后患者全血西罗莫司浓度,以及西罗莫司对血常规、肝肾功能、血脂和尿蛋白的影响进行分析。结果:294例次全血西罗莫司浓度中有206例次（70%）在3～8ng·ml^-1范围内。肾移植6个月后,全血西罗莫司浓度测定值随移植时间延长而降低。服用西罗莫司后的尿蛋白数值升高,与服用之前相比差异有统计学意义（P<0.05或0.01）。结论:全血西罗莫司谷浓度治疗窗:术后1～3个月为4～6ng·ml^-1,第4～6个月为3～6ng·ml^-1,>6个月为3～5ng·ml^-1。     

CNI induced Th17/Treg imbalance and susceptibility to renal dysfunction in renal transplantation

Calcineurin inhibitors (CNI) prevent graft rejection by blocking interleukin-2 (IL-2), which was required for development and function of Foxp3⁺CD4⁺CD25⁺ regulatory T cells (Treg). Recently, IL-2 was reported to play a part in the inhibition of Th17 cells. The renal transplantation recipient who used CNI regularly might have Th17/Treg imbalance with increased Th17 cells and decreased Treg cells, which would cause renal dysfunction even rejection. To assess the effect of CNI on Th17 cells and Treg cells, we included 123 renal transplantation recipients (101 in a stable stage and 22 with renal dysfunction) and 27 healthy volunteers. Among all the recipients, 103 recipients used CNI and 20 recipients used sirolimus without CNI. The recipients who used CNI were further classified into four groups according to the blood levels of CNI: Of all these subjects, Th17 and Treg frequencies in the peripheral blood were analyzed by flow cytometry (FCM). Serums IL-17, IL-23, IL-6, IFN-r, and TGF-β were analyzed by ELISA. The results demonstrated that the transplantation recipient treated by CNI revealed an obvious increase in peripheral Th17 frequencies and a significant decrease in Treg frequencies when compared with the sirolimus group and healthy people (P < 0.05). Even more, the transplantation recipient with renal dysfunction had the highest level of Th17 cells (P < 0.05) while the lowest Treg cells compared with stable recipient and healthy control, with increased serums IL-6 and IL-17. Our results indicated that CNI was associated with Th17/Treg imbalance in peripheral blood, which supported the followed generation of renal dysfunction after transplantation.     

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus

Objective Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine.Methods In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing.Results Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77–0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83–0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%.Conclusions Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.