title: Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratios.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine II--Cardiology, University of Ulm, Ulm, Germany. rainer.voisard@uni-ulm.de
authors.forename: Rainer
authors.initials: R
authors.lastname: Voisard
authors.forename: Svenja
authors.initials: S
authors.lastname: Zellmann
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Felicitas
authors.initials: F
authors.lastname: Fahlisch
authors.forename: Lutz
authors.initials: L
authors.lastname: von Müller
authors.forename: Regine
authors.initials: R
authors.lastname: Baur
authors.forename: Jürgen
authors.initials: J
authors.lastname: Braun
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gschwendt
authors.forename: Margaratis
authors.initials: M
authors.lastname: Kountides
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Hombach
authors.forename: Joachim
authors.initials: J
authors.lastname: Kamenz
mesh_terms: D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D012077:Renal Artery / Q000166:cytology / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D015607:Stents / Q000706:statistics & numerical data
chemical_list: D020123:Sirolimus