Voisard Rainer, Zellmann Svenja, Müller Fabian, Fahlisch Felicitas, von Müller Lutz, Baur Regine, Braun Jürgen, Gschwendt Jürgen, Kountides Margaratis, Hombach Vinzenz, Kamenz Joachim
Department of Internal Medicine II--Cardiology, University of Ulm, Ulm, Germany.
BMC Cardiovasc Disord. 2007 May 11;7:15. doi: 10.1186/1471-2261-7-15.
Sirolimus (SRL, Rapamycin) has been used successfully to inhibit restenosis both in drug eluting stents (DES) and after systemic application. The current study reports on the effects of SRL in various human in vitro/ex vivo models and evaluates the theoretical clinical relevance of the data by SI/MPL- and SI/DES-ratio's.
Definition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (6.4 ng/ml for SRL). Definition of the SI/DES-ratio: relation between significant inhibitory effects in vitro/ex vivo and the drug concentration in DES (7.5 mg/ml in the ISAR drug-eluting stent platform). Part I of the study investigated in cytoflow studies the effect of SRL (0.01-1000 ng/ml) on TNF-alpha induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of SRL (0.01-1000 ng/ml) on cell migration of HCMSMC. In part III, IV, and V of the study ex vivo angioplasty (9 bar) was carried out in a human organ culture model (HOC-model). SRL (50 ng/ml) was added for a period of 21 days, after 21 and 56 days cell proliferation, apoptosis, and neointimal hyperplasia was studied.
Expression of ICAM-1 was significantly inhibited both in HCAEC (SRL > or = 0.01 ng/ml) and HCMSMC (SRL > or = 10 ng/ml). SRL in concentrations > or = 0.1 ng/ml significantly inhibited migration of HCMSMC. Cell proliferation and neointimal hyperplasia was inhibited at day 21 and day 56, significance (p < 0.01) was achieved for the inhibitory effect on cell proliferation in the media at day 21. The number of apoptotic cells was always below 1%.
SI/MPL-ratio's < or = 1 (ICAM-1 expression, cell migration) characterize inhibitory effects of SRL that can be theoretically expected both after systemic and local high dose administration, a SI/MPL-ratio of 7.81 (cell proliferation) represents an effect that was achieved with drug concentrations 7.81-times the MPL. SI/DES-ratio's between 10-6 and 10-8 indicate that the described inhibitory effects of SRL have been detected with micro to nano parts of the SRL concentration in the ISAR drug-eluting stent platform. Drug concentrations in DES will be a central issue in the future.
西罗莫司（SRL，雷帕霉素）已成功用于抑制药物洗脱支架（DES）中的再狭窄以及全身应用后的再狭窄。本研究报告了西罗莫司在各种人体体外/离体模型中的作用，并通过SI/MPL比和SI/DES比评估了数据的理论临床相关性。
SI/MPL比的定义：体外/离体显著抑制作用与体内全身给药后最大血浆水平（西罗莫司为6.4 ng/ml）之间的关系。SI/DES比的定义：体外/离体显著抑制作用与DES中药物浓度（ISAR药物洗脱支架平台中为7.5 mg/ml）之间的关系。研究的第一部分在细胞流式研究中调查了西罗莫司（0.01 - 1000 ng/ml）对人冠状动脉内皮细胞（HCAEC）和人冠状动脉平滑肌细胞（HCMSMC）中肿瘤坏死因子-α诱导的细胞间粘附分子1（ICAM-1）表达的影响。研究的第二部分分析了西罗莫司（0.01 - 1000 ng/ml）对HCMSMC细胞迁移的影响。在研究的第三、四和五部分中，在人体器官培养模型（HOC模型）中进行体外血管成形术（9 bar）。加入西罗莫司（50 ng/ml）持续21天，在21天和56天后研究细胞增殖、凋亡和新生内膜增生。
在HCAEC（西罗莫司≥0.01 ng/ml）和HCMSMC（西罗莫司≥10 ng/ml）中，ICAM-1的表达均受到显著抑制。浓度≥0.1 ng/ml的西罗莫司显著抑制HCMSMC的迁移。在第21天和第56天，细胞增殖和新生内膜增生受到抑制，在第21天对培养基中细胞增殖的抑制作用达到显著水平（p < 0.01）。凋亡细胞数量始终低于1%。
SI/MPL比≤1（ICAM-1表达、细胞迁移）表明西罗莫司的抑制作用在全身和局部高剂量给药后在理论上均可预期，SI/MPL比为7.81（细胞增殖）代表了在药物浓度为MPL的7.81倍时所达到的效果。SI/DES比在10 - 6至10 - 8之间表明，在ISAR药物洗脱支架平台中，已检测到西罗莫司在微摩尔至纳摩尔浓度下具有所述的抑制作用。DES中的药物浓度将是未来的一个核心问题。
