Abstract
BackgroundSirolimus (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.MethodsDefinition 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-α 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.ResultsExpression of ICAM-1 was significantly inhibited both in HCAEC (SRL ≥ 0.01 ng/ml) and HCMSMC (SRL ≥ 10 ng/ml). SRL in concentrations ≥ 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%.ConclusionSI/MPL-ratio's ≤ 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.
Highlights
Sirolimus (SRL, Rapamycin) has been used successfully to inhibit restenosis both in drug eluting stents (DES) and after systemic application
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
Effect of SRL on intercellular adhesion molecule 1 (ICAM-1) expression in human coronary endothelial cells (HCAEC), HUVEC, and HCMSMC The effects of SRL (0.01, 0.1, 1, 10, 100, 1000 ng/ml) on the tumor necrosis factor-α (TNF-α) induced expression of ICAM-1 are demonstrated in figure 1
Summary
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. Sirolimus (SRL, rapamycin) was initially developed as an antibiotic, as an immunosuppressant, and recently has been identified as one of the most promising novel agents for prevention of human coronary restenosis, both as the compound in drug eluting stents (DES) or after systemic administration. In a very short period of time after these initial reports positive effects of SRL were described in animal [3,4] and clinical restenosis studies, using SRL eluting stents [5] or systemic administration [6,7]. Nührenberg et al [11] used the HOC-model to demonstrate that SRL in a concentration of 100 ng/ml combines antiproliferative and antiinflammatory properties
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