Everolimus: An update on the mechanism of action, pharmacokinetics and recent clinical trials

Expert Opinion on Drug Metabolism and Toxicology

Volumn 4, Issue 6, 2008, Pages 807-819

  Sánchez Fructuoso, Ana I ^a  

^a Hospital Clinico   (Spain)

Author keywords

Everolimus; Immunosuppresive drugs; mTOR inhibitors; Proliferation signal inhibitors; RAD; Renal transplantation

Indexed keywords

AZATHIOPRINE; BASILIXIMAB; BELATACEPT; CALCINEURIN INHIBITOR; CARBAMAZEPINE; CORTICOSTEROID; CYCLOSPORIN A; DEXAMETHASONE; ERYTHROMYCIN; EVEROLIMUS; KETOCONAZOLE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; PHENOBARBITAL; PHENYTOIN; PLACEBO; PREDNISONE; RAPAMYCIN; RIFAMPICIN; RITONAVIR; TACROLIMUS; VERAPAMIL;

ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ARTHRALGIA; ARTICLE; CHRONIC ALLOGRAFT NEPHROPATHY; CLINICAL TRIAL; COCHRANE LIBRARY; CYTOMEGALOVIRUS INFECTION; DIARRHEA; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG ERUPTION; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SUBSTITUTION; DRUG WITHDRAWAL; EDEMA; EMBASE; EVIDENCE BASED MEDICINE; FATIGUE; FOOD DRUG INTERACTION; GASTROINTESTINAL SYMPTOM; GRAPEFRUIT JUICE; HEART TRANSPLANTATION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; INTERSTITIAL PNEUMONIA; KIDNEY ALLOGRAFT REJECTION; KIDNEY DYSFUNCTION; KIDNEY TRANSPLANTATION; LIVER DISEASE; LOADING DRUG DOSE; LONG TERM CARE; LOW DRUG DOSE; LYMPHOCELE; MEDLINE; MOUTH ULCER; MUCOSA INFLAMMATION; NAUSEA; NEPHROTOXICITY; NONHUMAN; ORGAN TRANSPLANTATION; PERICARDIAL EFFUSION; PNEUMONIA; PROTEINURIA; SINGLE DRUG DOSE; SYSTEMATIC REVIEW; THROMBOCYTOPENIA; THROMBOSIS; WOUND DEHISCENCE; WOUND HEALING IMPAIRMENT; WOUND INFECTION;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; CYTOMEGALOVIRUS INFECTIONS; DRUG MONITORING; GRAFT REJECTION; GRAFT SURVIVAL; HEART TRANSPLANTATION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; NEOPLASMS; ORGAN TRANSPLANTATION; SIROLIMUS; TREATMENT OUTCOME;

EID: 48949117156     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.4.6.807     Document Type: Article

References (144)

1. Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997;64:36-42
2. Schuurman HJ, Schuler W, Ringers J, Jonker M. The macrolide SDZ RAD is efficacious in a nonhuman primate model of allotransplantation. Transplant Proc 1998;30:2198-9
3. Cole OJ, Shehata M, Rigg KM. Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 1998;30:2200-3
4. Vítko S, Margreiter R, Weimar W, et al. RAD B201 Study Group. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005;5:2521-30
5. Lorber MI, Mulgaonkar S, Butt KM, et al. B251 Study Group. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, Phase III study. Transplantation 2005;80:244-52
6. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004;4:626-35
7. Vigan M, Tuzcu M, Benza R, et al. RAD B253 Study Group. Prevention of acute rejection and allograft vasculopathy by everolimus in cardiac transplants recipients: a 24-month analysis. J Heart Lung Transplant 2007;26:584-92
8. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975;28:721-6
9. Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol 1977;55:48-51
10. Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989;17:609-10
11. Calne RY, Lim S, Saaman A, et al. Rapamycin for immunosuppression in organ allografting. Lancet 1989;2:227
12. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991;253:905-9
13. Abraham RT. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 1998;10:330-6
14. Sabers C, Martin M, Brunn G, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815-22
15. Sabatini D, Erdjument-Bromage H, Lui M, et al. A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35-43
16. Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Ann Rev Immunol 1996;14:483-510
17. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Soc Nephrol 1999;10:1366-80
18. Rovira P, Mascarell L, Truffa Bachi P. The impact of immunosuppressive drugs on the analysis of T cell activation. Curr Med Chem 2000;7:673-92
19. Crowe A, Bruelisauer A, Duerr L, et al. Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos 1999;27:627-32
20. Neumayer HH, Paradis K, Korn A, et al. Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol 1999;48:694-703
21. Kirchner GI, Winkler M, Mueller L, et al. Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD. Br J Clin Pharmacol 2000;50:449-54
22. Kahan BD, Wong RL, Carter C, et al. A phase I study of a 4-week course of SDZ-RAD (RAD) in quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation 1999;68:1100-6
23. Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001;69:48-56
24. Laplanche R, Meno-Tetang GM, Kawai R. Physiologically based pharmacokinetic (PBPK) modeling of everolimus (RAD001) in rats involving non-linear tissue uptake. J Pharmacokinet Pharmacodyn 2007;34:373-400
25. Jacobsen W, Serkova N, Hausen B, et al. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc 2001;33:514-5
26. Vidal C, Kirchner GI, Sewing KF. Structural elucidation by electrospray mass spectrometry: an approach to the in vitro metabolism of the macrolide immunosuppressant SDZ RAD. J Am Soc Mass Spectrom 1998;9:1267-74
27. Hallensleben K, Raida M, Habermehl G. Identification of a new metabolite of macrolide immunosuppressant, like rapamycin and SDZ RAD, using high performance liquid chromatography and electrospray tandem mass spectrometry. J Am Soc Mass Spectrom 2000;11:516-25
28. Lho st G, Hertsens R, Verbeeck RK, et al. In vitro immunosuppressive activity of tacrolimus dihydrodiol precursors obtained by chemical oxidation and identification of a new metabolite of SDZ-RAD by electrospray and electrospray-linked scan mass spectrometry. J Mass Spectrom 2001;36:889-90
29. Strom T, Haschke M, Zhang YL, et al. Identification of everolimus metabolite patterns in trough blood samples of kidney transplant patients. Ther Drug Monit 2007;29:592-9
30. Kovarik JM, Hartmann S, Figueiredo J, et al. Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy 2002;22:154-9
31. Kovarik JM, Hsu CH, McMahon L, et al. Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications. Clin Pharmacol Ther 2001;70:247-54
32. Van Damme-Lombaerts R, Webb NA, Hoyer PF, et al. Everolimus Study Group. Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients. Pediatr Transplant 2002;6:147-52
33. Hoyer PF, Ettenger R, Kovarik JM, et al. Everolimus Pediatric Study Group. Everolimus in pediatric de novo renal transplant patients. Transplantation 2003;75:2082-5
34. Kovarik JM, Kalbag J, Figueiredo J, et al. Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction. J Clin Pharmacol 2002;42:95-9
35. Kovarik JM, Curtis JJ, Hricik DE, et al. Differential pharmacokinetic interaction c tacrolimus and cyclosporine on everolimus. Transplant Proc 2006;38:3456-8
36. Kovarik JM, Beyer D, Bizot MN, et al. Pharmacokinetic interaction between verapamil and everolimus in healthy subjects. Br J Clin Pharmacol 2005;60:434-7
37. Kovarik JM, Beyer D, Bizot MN, et al. Effect of multiple-dose erythromycin on everolimus pharmacokinetics. Eur J Clin Pharmacol 2005;61:35-8
38. Kovarik JM, Beyer D, Bizot MN, et al. Blood concentrations of everolimus are markedly increased by ketoconazole. J Clin Pharmacol 2005;45:514-8
39. Kovarik JM, Hartmann S, Figueiredo J, et al. Effect of rifampin on apparent clearance of everolimus. Ann Pharmacother 2002;36:981-5
40. Kovarik JM, Beyer D, Schmouder RL. Everolimus drug interactions: application of a classification system for clinical decision making. Biopharm Drug Dispos 2006;27:421-6
41. Kovarik JM, Sabia HD, Figueiredo J, et al. Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 2001;70:425-3
42. Lorber MI, Ponticelli C, Whelchel J, et al. Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data. Clin Transplant 2005;19:145-52
43. Strom T, Haschke M, Boyd J, et al. Crossreactivity of isolated everolimus metabolites with the Innofluor Certican immunoassay for therapeutic drug monitoring of everolimus. Ther Drug Monit 2007;29:743-9
44. Salm P, Warnholtz C, Boyd J, et al. Evaluation of a fluorescent polarization immunoassay for whole blood everolimus determination using samples from renal transplant recipients. Clin Biochem 2006;39:732-8
45. Tenderich G, Fuchs U, Zittermann A, et al. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematologjcal parameters in heart transplant recipients. Clin Transplant 2007;21:536-43
46. Mueller MA, Beutner F, Teupser D, et al. Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR(-/-) mice despite severe hypercholesterolemia. Atherosclerosis 2007 [Epub ahead of print]
47. Tedesco-Silva H Jr, Vitko S, Pascual J, et al. 2306 and 2307 study groups. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transpl Int 2007;20:27-36
48. Montagnino G, Sandrini S, Iorio B, et al. A randomized exploratory trial of steroid avoidance in renal transplant patients treated with everolimus and low-dose cyclosporine. Nephrol Dial Transplant 2007 [Epub ahead of print]
49. Sánchez Fructuoso A, Calvo N, Moreno MA, et al. Study of anemia after late introduction of everolimus in the immunosuppressive treatment of renal transplant patients. Transplant Proc 2007;39:2242-4
50. Thaunat O, Beaumont C, Chatenoud L, et al. Anemia after late introduction of sirolimus may correlate with biochemical evidence chronic inflammatory state. Transplantation 2005;80:1212
51. Dean PG, Lund WJ, Larson TS, et al. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004;77:1555-61
52. Rothenburger M, Zuckermann A, Bara C, et al. Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second German-Austrian Certican Consensus Conference. J Heart Lung Transplant 2007;26:305-11
53. McTaggart RA, Tomlanovich S, Bostrom A, et al. Comparison of outcomes after delayed graft function: sirolimus-based versus other calcineurin-inhibitor sparing induction immunosuppression regimens. Transplantation 2004;78:475-80
54. Durrbach A, Rostaing L, Tricot L, et al. Prospective comparison of the use of sirolimus and cyclosporine in recipients of a kidney from an expanded criteria donor. Transplantation 2008;85:486-90
55. McTaggart RA, Gottlieb D, Brooks J, et al. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003;3:416
56. Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003;14:1037
57. Fuller TF, Freise CE, Serkova N, et al. Sirolimus delays recovery of rat kidney transplants after ischemia-reperfusion injury. Transplantation 2003;76:1594
58. Loverre A, Ditonno P, Crovace A, et al. Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. J Am Soc Nephrol 2004;15:2675
59. Pallet N, Thervet E, La Corre D, et al. Rapamycin inhibits human renal epithelial cell proliferation: effect on cyclin D3 mRNA expression and stability: Kidney Int 2005;67:2422
60. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75
61. David S, Kümpers P, Shin H, et al. Everolimus-associated interstitial pneumonitis in a patient with a heart transplant. Nephrol Dial Transplant 2007;22:3363-4
62. Morelon E, Stern M, Isra I-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001;72:787-90
63. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity: Transplantation 2004;77:1215-20
64. Vlahakis NE, Rickman OB, Morgenthaler T. Sirolimus-associated diffuse alveolar hemorrhage. Mayo Clin Proc 2004;79:541-5
65. Pascual J. Everolimus in clinical practice: renal transplantation. Nephrol Dial Transplant 2006;21(Suppl 3):iii18-23
66. Rehm B, Keller F, Mayer J, Stracke S. Resolution of sirolimus induced pneumonitis after conversion to everolimus. Transplant Proc 2006;38:711-3
67. Lehmkuhl H, Ross H, Eisen H, Valantine H. Everolimus (certican) in heart transplantation: optimizing renal function through minimizing cyclosporine exposure. Transplant Proc 2005;37:4145-9
68. Franco AF, Martini D, Abensur H, Noronha IL. Proteinuria in transplant patients associated with SRL. Transplant Proc 2007;39:449-52
69. Ruiz JC, Campistol JM, Sanchez-Fructuoso A, et al. Early SRL use with cyclosporine elimination does not induce progressive proteinuria. Transplant Proc 2007;39:2151-2
70. Aliabadi AZ, Pohanka E, Seebacher G, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant 2008;8:854-61
71. van den Akker JM, Wetzels JF, Hoitsma AJ. Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients. Kidney Int 2006;70:1355-7
72. Saurina A, Campistol JM, Piera C, et al. Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant 2006;2:488-93
73. Straathof-Galema L, Wetzels JF, Dijkman HB, et al. Sirolimus-associated heavy proteinuria in a renal transplant recipient: evidence for a tubular mechanism. Am J Transplant 2006;2:429-33
74. Dittrich E, Schmaldlienst S, Soleiman A, et al. Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int 2004;17:215-20
75. Schwarz C, Bohmig GA, Steininger R, et al. Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression. Nephrol Dial Transplant 2001;16:378-82
76. Vogelbacher R, Wittmann S, Braun A, et al. The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation 2007;84:1492-9
77. Lieberthal W, Fuhro R, Andry CC, et al. Rapamycin impairs recovery from acute renal failure: Role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol 2001;281:F693-706
78. Coombes JD, Mreich E, Liddle C, Rangan GK. Rapamycin worsens renal function and intratubular cast formation in protein overload nephropathy. Kidney Int 2005;68:2599-607
79. MacWay F, Coté I, Latulippe E, et al. Predisposing factors for sirolimus-induced proteinuria in renal transplant recipients [abstract]. Am J Transplant 2007;7(Suppl 2):246
80. Tuzuner A, Mead H, Sar A, et al. Clinical predictors for proteinuria development in patients converted to sirolimus base therapy [abstract]. Am J Transplant 2007;7(Suppl 2):447
81. Steele GH, Adamkovic AB, Demopoulos LA, et al. Pericardial effusion coincident with airolimus therapy: a review of Wyeth's safety database. Transplantation 2008;85:645-7
82. Chan L, Greenstein S, Hardy MA, et al. Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness. Transplantation 2008;85:821-6
83. Viklicky O, Zou H, Mueller V, et al. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation 2000;69:497-502
84. Lutz J, Zou H, Liu S, et al. Apoptosis and treatment of chronic allograft nephropathy with everolimus. Transplantation 2003;76:508-15
85. Sedrani R, Cottens S, Kallen J, Schuler W. Chemical modification of rapamycin; the discovery of SDZ-RAD. Transplant Proc 1998;30:2192-4
86. Salas-Prato M, Assalian A, Mehdi AZ, et al. Inhibition by rapamycin of PDGF- and bFGF-induced human tenon fibroblast proliferation in vitro. J Glaucoma 1996;5:54-9
87. Azzola A, Havryk A, Chhajed P, et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 2004;77:275-80
88. Ponticelli C. Can mTOR inhibitors reduce the risk of late kidney allograft failure? Transpl Int 2008;21:2-10
89. Mulay AV, Cockfield S, Stryker R, et al. Conversion from calcineurin inhibitors to SRL for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 2006;82:1153-62
90. Diekmann F, Campistol JM. Conversion from calcineurin inhibitors to SRL in chronic allograft nephropathy: benefits and risks. Nephrol Dial Transplant 2006;21:562-8
91. Wali RK, Mohanlal V, Ramos E, et al. Early withdrawal of calcineurin inhibitors and rescue immunosuppression with SRL-based therapy in renal transplant recipients with moderate to severe renal dysfunction. Am J Transplant 2007;7:1572-83
92. Kamar N, Frimat L, Blancho G, et al. Evaluation of the efficacy and safety of a slow conversion from calcineurin inhibitor- to SRL-based therapies in maintenance renal-transplant patients presenting with moderate renal insufficiency. Transpl Int 2007;20:128-34
93. Liu M, Zhang W, Gu M, et al. Protective effects of SRL by attenuating connective tissue growth factor expression in human chronic allograft nephropathy. Transplant Proc 2007;39:1410-5
94. Saber LT, Ikeda MY, Almeida JM. Posttransplantation conversion to SRL-based immunosuppression: a single center experience. Transplant Proc 2007;39:3098-100
95. Diekmann F, Budde K, Slowinski T, et al. Conversion to SRL for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria. Transpl Int 2008;21:152-5
96. Basu A, Falcone JL, Tan HP, et al. Chronic allograft nephropathy score before SRL rescue predicts allograft function in renal transplant patients. Transplant Proc 2007;39:94-8
97. Sánchez Fructuoso A, Ruiz San Millán JC, Calvo N, et al. Evaluation of the efficacy and safety of the conversion from a calcineurin inhibitor to an everolimus-based therapy in maintenance renal transplant patients. Transplant Proc 2007;39:2148-50
98. Ruiz JC, Sanchez-Fructuoso A, Rodrigo E, et al. Conversion to everolimus in kidney transplant recipients: a safe and simple procedure. Transplant Proc 2006;38:2424-6
99. Wirnsberger GH, Mauric A, Worm H, et al. Improvement of renal graft function after conversion to everolimus in long-term transplanted patients [abstract]. Transpl Int 2007;20(Suppl 2):255
100. Pape L, Ahlenstiel T, Ehrich JH, Offner G. Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low-dose cyclosporine A. Pediatr Transplant 2007;11:291-5
101. Morales J, Fierro A, Benavente D, et al. Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria. Transplant Proc 2007;39:591-3
102. Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in conversion from calcineurin inhibitor to SRL in chronic allograft dysfunction. Am J Transplant 2004;4:1869-75
103. Hiatt WR, Nissen SE. New drug application 21-628, Certican (everolimus), for the proposed indication of prophylaxis of rejection in heart transplantation: report from the Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration, November 16, 2005, Rockville, MD. Circulation 2006;113:e394-5
104. Wang S, Zuckermann A, Keogh AM, et al. Cyclosporine reduction in the presence of concentration-controlled everolimus in de novo cardiac transplantation: 6-month study results [abstract]. Transpl Int 2007;20(Suppl 2):94
105. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003;108:48-53
106. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomised clinical trial. Circulation 2004;110:2694-700
107. Schweiger M, Wasler A, Prenner G, et al. Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients. Transpl Immunol 2006;16:46-51
108. Ross HJ, Burton J, Pflugfelder R, et al. Canadian pilot study to determine safe and effective dosing of cyclosporine and everolimus in stable cardiac transplant recipients: twelve-week interim analysis [abstract]. J Heart Lung Transplant 2006;25:166
109. Trosch F, Rothenburger M, Schneider M, et al. First experience with rapamycin-based immunosuppression to improve kidney function after heart transplantation. Thorac Cardiovasc Surg 2004;52:163-8
110. Snell GI, Levvey BJ, Chin W, et al. Rescue therapy: a role for sirolimus in lung and heart transplant recipients. Transplant Proc 2001;33:1084-5
111. Bestetti R, Theodoropoulos TA, Burdmann EA, et al. Switch from calcineurin inhibitors to sirolimus-induced renal recovery in heart transplant recipients in the midterm follow-up. Transplantation 2006;81:692-6
112. Fernandez-Valls M, Gonzalez-Vilchez F, de Prada JA, et al. Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center. Transplant Proc 2005;37:4021-3
113. Groetzner J, Meiser B, Landwehr P, et al. Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac transplant recipients with chronic renal failure. Transplantation 2004;77:568-74
114. Hunt J, Lerman M, Magee MJ, et al. Improvement of renal dysfunction by conversion from calcineurin inhibitors to sirolimus after heart transplantation. J Heart Lung Transplant 2005;24:1863-7
115. Rothenburger M, Strypmann J, Welp H, et al. Calcineurin inhibitor-free immunosuppression using everolimus in long term heart transplant recipients: procedures of switching protocols and side effects [abstract]. J Heart Lung Transplant 2006;25:166
116. Kushwaha SS, Khalpey Z, Frantz RP, et al. Sirolimus in cardiac transplantation: use as a primary immunosuppressant in calcineurin inhibitor-induced nephrotoxicity. J Heart Lung Transplant 2005;24:2129-36
117. Moro J, Almenar L, Martínez-Dolz L, et al. mTOR inhibitors: do they help preserve renal function? Transplant Proc 2007;39:2135-7
118. MacDonald AS. Use of mTOR inhibitors in human organ transplantation. Expert Rev Clin Immunol 2007;3:423-36
119. Hummel M. Recommendations for use of Certican (everolimus) after heart transplantation: results from a German and Austrian Consensus Conference. J Heart Lung Transplant 2005;24 (Suppl 4):S196-200
120. Bocchi EA, Ahualli L, Amuchastegui M, et al. Recommendations for use of everolimus after heart transplantation: results from a Latin-American Consensus Meeting. Transplant Proc 2006;38:937-4
121. Fiocchi R, Iacovoni A, Sebastiani R, et al. Possible role of everolimus in improving renal function in long-term heart transplantation. Transplant Proc 2007;39:1967-9
122. Snell GI, Valentine VG, Vitulo P, et al. RAD B159 Study Group. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006;6:169-77
123. Levy GA, Grant D, Paradis K, et al. Pharmacokinetics and tolerability of 40-0[2-hydroxyethyl]rapamycin in de novo liver transplant recipients. Transplantation 2001;71:160-3
124. Levy G, Schmidli H, Punch J, et al. Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results. Liver Transpl 2006;12:1640-8
125. Rapamune oral solution - Sirolimus - Wyeth Pharmaceuticals. In: Physician desk reference 2003. 57th edition. Montvale, NJ: Thomson Healthcare; 2003. p. 3469-74
126. Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and metaanalysis of randomized trials. Transplantation 2006;81:1234-48
127. Hill JA, Hummel M, Starling RC, et al. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation 2007;84:1436-42
128. Valantine H. Is there a role for proliferation signal/mTOR inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology. J Heart Lung Transplant 2007;26:557-64
129. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med 2007;13:433-42
130. Albanell J, Dalmases A, Rovira A, Rojo F. mTOR signalling in human cancer. Clin Transl Oncol 2007;9:484-93
131. Seeliger H, Guba M, Kleespies A, et al. Rnle of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 2007;26:611-21
132. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128-35
133. Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002;62:5027
134. Boulay A, Stephan C, Zumstein-Mecker S. Phospho-Akt levels as a potential biomarker of in vitro sensitivity of tumor cell lines to the mTOR pathway inhibitor RAD001 [abstract B170]. Clin Cancer Res 2003;9
135. Awada A, Cardoso F, Fontaine C, et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 2008;44:84-91
136. Haritunians T, Mori A, O'Kelly J, et al. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2007;21:333-9
137. Fouladi M, Laningham F, Wu J, et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol 2007;25:4806-12
138. Gomez-Camarero J, Salcedo M, Rincon D, et al. Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. Transplantation 2007;84:786-91
139. de Fijter JW. Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation. Nephrol Dial Transplant 2007;22 (Suppl 1):i23-6
140. Ruiz JC, Sánchez A, Rengel M, et al. EVERODATA Group. Use of the new proliferation signal inhibitor everolimus in renal transplant patients in Spain: preliminaty results of the EVERODATA registry. Transplant Proc 2007;39:2157-9
141. Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 2003;75:1710-7
142. Jundt F, Raetzel N, Müller C, et al. A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein beta and NF-kappa B activity in Hodgkin and anaplastic large cell lymphomas. Blood 2005;106:1801-7
143. Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 2007;85:54-60
144. Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 2007;13:4261-70