Abstract
Background: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. Methods: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. Results: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5–1.5 mg/kg/day) or imatinib (2– 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. Conclusions: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.
References
1.
Hausleiter J, Kastrati A, Mehilli J, Schuhlen H, Pache J, Dotzer F, Sattelberger U, Dirschinger J, Schomig A: Impact of lesion complexity on the capacity of a trial to detect differences in stent performance: results from the ISAR- STEREO trial. Am Heart J 2003;146:882–886.
2.
Schuhlen H, Kastrati A, Mehilli J, Hausleiter J, Pache J, Dirschinger J, Schomig A: Restenosis detected by routine angiographic follow-up and late mortality after coronary stent placement. Am Heart J 2004;147:317–322.
3.
Sheiban I, Moretti C, Kumar P, Gagnor A, Leonardo F, Montaldo T, Marra WG, Omede P, Trevi G: Immediate and medium-term outcomes following the treatment of very long (> or = 50 mm) chronic total coronary artery occlusions. J Invasive Cardiol 2004;16:5–9.
4.
Albiero R, Silber S, Di Mario C, Cernigliaro C, Battaglia S, Reimers B, Frasheri A, Klauss V, Auge JM, Rubartelli P, Morice MC, Cremonesi A, Schofer J, Bortone A, Colombo A, RESCUT investigators: Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis: results of the restenosis cutting balloon evaluation trial (RESCUT). J Am Coll Cardiol 2004;43:943–949.
5.
Uetani T, Ishii H, Sakai S, Watanabe J, Kanashiro M, Ichimiya S, Murohara T, Matsubara T: Beneficial effect of rotational atherectomy with low platform speed on late outcomes. Int J Cardiol 2004;94:35–40.
6.
Julius BK, Attenhofer Jost CH, Sutsch G, Brunner HP, Kuenzli A, Vogt PR: Incidence, progression and functional significance of cardiac allograft vasculopathy after heart transplantation. Transplantation 2000;69:847–853.
7.
Gregory CR, Huie P, Billingham ME, Morris RE: Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury: its effect on cellular, growth factor and cytokine responses in injured vessels. Transplantation 1993;55:1409–1418.
8.
Burke SE, Lubbers NL, Chen YW, Hsieh GC, Mollison KW, Luly JR, Wegner CD: Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin. J Cardiovasc Pharmacol 1999;33:829–835.
9.
Gallo R, Padurean A, Jayaraman T, Marx S, Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A, Badimon JJ: Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999;99:2164–2170.
10.
Roque M, Reis ED, Cordon-Cardo C, Taubman MB, Fallon JT, Fuster V, Badimon JJ: Effect of p27 deficiency and rapamycin on intimal hyperplasia: in vivo and in vitro studies using a p27 knockout mouse model. Lab Invest 2001;81:895–903.
11.
Schmid C, Heemann U, Azuma H, Tilney NL: Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation 1995;60:729–733.
12.
Poston RS, Billingham M, Hoyt EG, Pollard J, Shorthouse R, Morris RE, Robbins RC: Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 1999;100:67–74.
13.
Ikonen TS, Gummert JF, Hayase M, Honda Y, Hausen B, Christians U, Berry GJ, Yock PG, Morris RE: Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates. Transplantation 2000;70:969–975.
14.
Ikonen TS, Gummert JF, Serkova N, Hayase M, Honda Y, Kobayase Y, Hausen B, Yock PG, Christians U, Morris RE: Efficacies of sirolimus (rapamycin) and cyclosporine in allograft vascular disease in non-human primates: trough levels of sirolimus correlate with inhibition of progression of arterial intimal thickening. Transpl Int 2000;13:S314–S320.
15.
Dambrin C, Klupp J, Birsan T, Luna J, Suzuki T, Lam T, Stahr P, Hausen B, Christians U, Fitzgerald P, Berry G, Morris R: Sirolimus (rapamycin) monotherapy prevents graft vascular disease in nonhuman primate recipients of orthotopic aortic allografts. Circulation 2003;107:2369–2374.
16.
Murphy GJ, Bicknell GR, Nicholson ML: Rapamycin inhibits vascular remodeling in an experimental model of allograft vasculopathy and attenuates associated changes in fibrosis-associated gene expression. J Heart Lung Transplant 2003;22:533–541.
17.
Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, Edwards N, Oz M, Marks AR: Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003;108:48–53.
18.
Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmaz S, Häyry P, Neylan JF, Rapamune Maintenance Regimen Trial: Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 2004;4:953–961.
19.
Brara PS, Moussavian M, Grise MA, Reilly JP, Fernandez M, Schatz RA, Teirstein PS: Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation 2003;107:1722–1724.
20.
Rodriguez AE, Alemparte MR, Vigo CF, Pereira CF, Llaurado C, Russo M, Virmani R, Ambrose JA: Pilot study of oral rapamycin to prevent restenosis in patients undergoing coronary stent therapy: Argentina Single-Center Study (ORAR trial). J Invasive Cardiol 2003;15:581–584.
21.
Sousa JE, Costa MA, Abizaid AC, Rensing BJ, Abizaid AS, Tanajura LF, Kozuma K, van Langenhove G, Sousa AG, Falotico R, Jaeger J, Popma JJ, Serruys PW: Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001;104:2007–2011.
22.
Morice MC, Serruys PW, Sousa JE, Fajadet J, Hayashi EB, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R, the RAVEL Study Group: A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
23.
Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE, the SIRIUS Investigators: Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
24.
Bhatia V, Bhatia R, Dhindsa M: Drug-eluting stents: new era and new concerns. Postgrad Med J 2004;80:13–18.
25.
Gregory CR, Huang X, Pratt RE, Dzau VJ, Shorthouse R, Billingham ME, Morris RE: Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995;59:655–661.
26.
Gregory CR, Katznelson S, Griffey SM, Kyles AE, Berryman ER: Fluvastatin in combination with RAD significantly reduces graft vascular disease in rat cardiac allografts. Transplantation 2001;72:989–993.
27.
Sihvola R, Koskinen P, Myllärniemi M, Loubtchenkov M, Häyry P, Buchdunger E, Lemström K: Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor. Circulation 1999;99:2295–2301.
28.
Sihvola RK, Tikkanen JM, Krebs R, Aaltola EM, Buchdunger E, Laitinen O, Koskinen PK, Lemström KB: Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits. Transplantation 2003;75:334–339.
29.
Myllärniemi M, Calderon L, Lemström K, Buchdunger E, Häyry P: Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation. FASEB J 1997;11:1119–1126.
30.
Capron L, Bruneval P: Influence of applied stress on mitotic response of arteries to injury with a balloon catheter: quantitative study in rat thoracic aorta. Cardiovasc Res 1989;23:941–948.
31.
Maleki S, Graves S, Becker S, Horwatt R, Hicks D, Stroshane RM, Kincaid H: Therapeutic monitoring of sirolimus in human whole-blood samples by high-performance liquid chromatography. Clin Ther 2000;22:B25–B37.
32.
Farb A, John M, Acampado E, Kolodgie FD, Prescott MF, Virmani R: Oral everolimus inhibits in-stent neointimal growth. Circulation 2002;106:2379–2384.
33.
Shaw LM, Kaplan B, Brayman KL: Advances in therapeutic drug monitoring for immunosuppressants: a review of sirolimus. Clin Ther 2000;22:B1–B13.
34.
Chan CC, Martin DF, Xu D, Roberge FG: Side effects of rapamycin in the rat. J Ocul Pharmacol Ther 1995;11:177–181.
35.
Walpoth BH, Pavlicek M, Celik B, Nicolaus B, Schaffner T, Althaus U, Hess OM, Carrel T, Morris RE: Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts. Eur J Cardiothorac Surg 2001;19:487–492.
36.
Crowe A, Bruelisauer A, Duerr L, Guntz P, Lemaire M: Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos 1999;27:627–632.
37.
Sano H, Sudo T, Yokode M, Murayama T, Kataoka H, Takakura N, Nishikawa S, Nishikawa S, Kita T: Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice. Circulation 2001;103:2955–2960.
38.
Ferns GA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 1991;253:1129–1132.
39.
Lemström KB, Koskinen PK: Expression and localization of platelet-derived growth factor ligand and receptor protein during acute and chronic rejection of rat cardiac allografts. Circulation 1997;96:1240–1249.
40.
Kallio EA, Koskinen PK, Aavik E, Buchdunger E, Lemström KB: Role of platelet-derived growth factor in obliterative bronchiolitis (chronic rejection) in the rat. Am J Respir Crit Care Med 1999;160:1324–1332.
41.
Savikko J, Taskinen E, Von Willebrand E: Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy. Transplantation 2003;75:1147–1153.
42.
Berenbaum MC: Synergy, additivism and antagonism in immunosuppression: a critical review. Clin Exp Immunol 1977;28:1–18.
43.
Zernecke A, Schober A, Bot I, von Hundelshausen P, Liehn EA, Mopps B, Mericskay M, Gierschik P, Biessen EA, Weber C: SDF-1α/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells. Circ Res 2005;96:784–791.
44.
Fukuda D, Sata M, Tanaka K, Nagai R: Potent inhibitory effect of sirolimus on circulating vascular progenitor cells. Circulation 2005;111:926–931.
45.
DiJoseph JF, Fluhler E, Armstrong J, Sharr M, Sehgal SN: Therapeutic blood levels of sirolimus (rapamycin) in the allografted rat. Transplantation 1996;62:1109–1112.
46.
O’Brien SG, Meinhardt P, Bond E, Beck J, Peng B, Dutreix C, Mehring G, Milosavljev S, Huber C, Capdeville R, Fischer T: Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 2003;89:1855–1859.
47.
Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG, Neel BG: Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 2004;101:3130–3135.
© 2006 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
