Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>Definition of the SI/MPL-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the <b>m</b>aximal <b>p</b>lasma <b>l</b>evel after systemic administration in vivo (6.4 ng/ml for SRL). Definition of the SI/DES-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the drug concentration in <b>DES </b>(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.</p> <p>Results</p> <p>Expression 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%.</p> <p>Conclusion</p> <p>SI/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^-6and 10^-8indicate 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.</p

In the ex vivo HOC-model the effect of a 21 days incubation with SRL (50 ng/ml) on reactive cell proliferation was studied in the neointima, plaque-intima, and media at day 21 and day 56

<p><b>Copyright information:</b></p><p>Taken from "Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's"</p><p>http://www.biomedcentral.com/1471-2261/7/15</p><p>BMC Cardiovascular Disorders 2007;7():15-15.</p><p>Published online 11 May 2007</p><p>PMCID:PMC1878500.</p><p></p> SRL inhibited reactive cell proliferation, statistical significance was achieved for the inhibitory effect on cell proliferation in the media at day 21 (SI/MPL-ratio: 7.81)

The effect of incubation of the ex vivo HOC-model with SRL (50 ng/ml) on apoptosis was studied in the neointima, plaque-intima, and media at day 21 and day 56

<p><b>Copyright information:</b></p><p>Taken from "Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's"</p><p>http://www.biomedcentral.com/1471-2261/7/15</p><p>BMC Cardiovascular Disorders 2007;7():15-15.</p><p>Published online 11 May 2007</p><p>PMCID:PMC1878500.</p><p></p

In the ex vivo HOC-model the effect of 21 days incubation with SRL (50 ng/ml) on neointimal hyperplasia was studied 21 days and 56 days after ballooning

<p><b>Copyright information:</b></p><p>Taken from "Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's"</p><p>http://www.biomedcentral.com/1471-2261/7/15</p><p>BMC Cardiovascular Disorders 2007;7():15-15.</p><p>Published online 11 May 2007</p><p>PMCID:PMC1878500.</p><p></p> SRL inhibited neointimal hyperplasia, statistical significance was not achieved