Since the early 1980s, the combination of cyclosporine, azathioprine, and prednisone has been the mainstay tripledrug immunosuppressive regimen used in transplantation. However, advances in drug research, design, and development have allowed for the introduction of new agents that have greatly increased the number of immunosuppressive agents available for use in transplant recipients. Particularly, the newer antiproliferative immunosuppressive drugs (agents that directly inhibit the proliferation of T and B lymphocytes) have had an important impact on patient outcomes posttransplant. These agents are mycophenolate mofetil and sirolimus.
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References
1.
1. Allison AC, Hovi T, Watts RWE, Webster ADB. Immunological observations on patients with Lesch-Nyhan syndrome, and on the role of de novo purine synthesis in lymphocyte transformation. Lancet. 1975;2:1179-1182.
2.
2. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972;2:1067-1069.
3.
3. Carter SB, Franklin TJ, Jones DF, et al. Mycophenolic acid: an anti-cancer compound with unusual properties [abstract]. Nature. 1969;23:848-850.
4.
4. Allison AC, Eugui EM. The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin Immunopathol. 1993;14:353-380.
5.
5. Franklin TJ, Cook JM. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J. 1969;113:515-524.
6.
6. Sweeney MJ, Hoffman DH, Esterman MA. Metabolism and biochemistry of mycophenolic acid. Cancer Res. 1972;32:1803-1809.
7.
7. Verham R, Meek TD, Hedstrom L, Wang CC. Purification, characterization, and kinetic analysis of inosine 5’-monophosphate dehydrogenase of Tritichomonas foetus. Mol Biochem Parasitol. 1987;24:1-12.
8.
8. Allison AC, EuguiEM, ThomsonAW, Starzl TF. Mycophenolate mofetil (RS-61443): mode of action and effects on graft rejection. In: Thomson A et al, eds. Immunosuppressive Drugs: Developments in Anti-rejection Therapy. New York: Edward Arnold; 1994:141-141.
9.
9. Allison AC, Almquist SJ, Muller CD, Eugui EM. In vitro immunosuppressive effects of mycophenolic acid and an ester pro-drug, RS-61443. Transplant Proc. 1991;23(suppl 2):10-14.
10.
10. Eugui EM, Almquist SJ, Muller CD, et al. Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand J Immunol. 1991;33:161-173.
11.
11. Dayton JS, Turka LA, Thompson CB, et al. Comparison of the effects of mizoribine with those of azathioprine, 6-mercaptopurine, and mycophenolic acid on lymphocyte-T proliferation and purine ribonucleotide metabolism. Mol Pharmacol. 1992;41:671-676.
12.
12. Franchetti P, GrifantiniM. Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents. Curr Med Chem. 1999;6:599-614.
13.
13. Griesmacher A, Weigel G, Seebacher G, Muller MM. IMPdehydrogenase inhibition in human lymphocytes and lymphoblasts by mycophenolic acid and mycophenolic acid glucuronide. Clin Chem. 1997;43:2312-2317.
14.
14. Laski LA. Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science. 1992;258:964-964.
15.
15. Wyss D, Choi JS, Li J, et al. Conformation and function of the N-linked glycan in the adhesion domain of human CD2. Science. 1995;269:1273-1273.
16.
16. Allison AC, Kowalski WJ, Muller CJ, Waters RV, Eugui EM. Mycophenolic acid and brequinar, inhibitors of purine and pyrimidine synthesis, block the glycosylation of adhesion molecules. Transplant Proc. 1993;2:67-67.
17.
17. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant. 1996;10:77-84.
18.
18. Laurent AF, Dumont S, Poindron P, Muller CD. Mycophenolic acid suppresses protein N-linked glycosylation in human monocytes and their adhesion to endothelial cells and to some substrates. Exp Hematol. 1996;24:59-67.
19.
19. Eugui EM, Mirkovich A, Allison AC. Lymphocyte-selective antiproliferative and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol. 1991;33:175-175.
20.
20. Eugui EM, Nakano G, Byars NE. Effect of mycophenolic acid on antibody titers and isotypes in mice vaccinated with influenza virus hemagglutinin [abstract]. In: Proceedings of 9th International Congress of Immunology, San Francisco. 1995;855-855.
21.
21. Burlingham WJ, Grailer AP, Hullett DA, Sollinger HW. Inhibition of both MLC and in vitro IgG memory response to tetanus toxoid by RS-61443. Transplantation. 1991;51:545-547.
22.
22. Eugui EM, Almquist SJ, Mulle CD, Allison AC. Lymphocyteselective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand J Immunol. 1991;33:161-173.
23.
23. Grailer A, Nichols J, Hullett D, SollingerHW, Burlingham WJ. Inhibition of human B cell responses in vitro by RS-61443, cyclosporine A and DAB486 IL-2. Transplant Proc. 1991;23: 314-315.
24.
24. Raisanen-Sokolowski A, Myllarniemi M, Hayry P. Effect of mycophenolate mofetil on allograft arteriosclerosis (chronic rejection). Transplant Proc. 1994;26:3225-3225.
25.
25. Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, Yilmaz S, Kallio E, Hayry P. Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle cell proliferation in rat aorticallografts. Transplant Immunol. 1995;3:342-351.
26.
26. Raisanen-Sokolowski A, Aho P, Myllarniemi M, Kallio E, Hayry P. Inhibition of early chronic rejection in rat aortic allografts by mycophenolate mofetil (RS61443). Transplant Proc. 1995;27: 435-435.
27.
27. Mohacsi PJ, Tuller D, Hulliger B, Wijngaard PL. Different inhibitory effects of immunosuppressive drugs on human and rat aortic smooth muscle and endothelial cell proliferation stimulated by platelet-derived growth factor or endothelial cell growth factor. J Heart Lung Transplant. 1997;16:484-492.
28.
28. Lee WA, Gu L, Miksztal AR, et al. Bioavailability improvement of mycophenolic acid through amino ester derivitization. Pharmacol Res. 1990;7:161-166.
29.
29. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998; 34(6):429-455.
30.
30. Goodkin DE, Bailly RC, Teetzen ML, Hertsgaard D, Beatty WW. The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology. 1991;41:20-25.
31.
31. Nowak I, Shaw L. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem. 1995;41:1011-1017.
32.
32. Weber LT, Shipkova M, Lamersdorf T, et al. Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatricand adult renal transplant recipients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. J Am Soc Nephrol. 1998;9:1511-1520.
33.
33. Weber LT, Lamersdorf T, Shipkova M, et al. Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatricpatients. German Study Group onMycophenolateMofetil Therapy in PediatricRenal Transplant Recipients. Ther Drug Monit. 1999;21:498-506.
34.
34. Weber LT, Schutz E, Lamersdorf T, et al. Therapeutic drug monitoring of total and free mycophenolic acid (MPA) and limited sampling strategy for determination of MPA-AUC in paediatric renal transplant recipients. The German Study Group on Mycophenolate Mofetil (MMF) Therapy. Nephrol Dial Transplant. 1999;14(suppl 4):34-35.
35.
35. Weber LT, Schutz E, Lamersdorf T, et al. Pharmacokinetics of mycophenolic acid (MPA) and free MPA in paediatric renal transplant recipients. A multicenter study. The German Study Group onMycophenolateMofetil (MMF) Therapy. Nephrol Dial Transplant. 1999;14(suppl 4):33-34.
36.
36. Meier-Kriesche HU, Shaw LM, Korecka M, Kaplan B. Pharmacokinetics of mycophenolic acid in renal insufficiency. Ther Drug Monit. 2000;22:27-30.
37.
37. Kaplan B, Gruber SA, Nallamathou R, Katz SM, Shaw LM. Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure. Transplantation. 1998;65:1127-1129.
39. Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T. Current issues in therapeuticdrug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit. 2001;23:305-315.
40.
40. DeNofrio D, Loh E, Kao A, et al. Mycophenolic acid concentrations are associated with cardiac allograft rejection. JHeart Lung Transplant. 2000;19:1071-1076.
41.
41. YamaniMH, Starling RC, GoormasticM, et al. The impact of routine mycophenolate mofetil drug monitoring on the treatment of cardiac allograft rejection. Transplantation. 2000;69:2326-2330.
42.
42. Mourad M, Malaise J, Chaib Eddour D, De Meyer M, et al. Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem. 2001;47:88-94.
43.
43. Cattaneo D, Gaspari F, Ferrari S, et al. Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients. Clin Transplant. 2001;15:402-409.
44.
44. Pawinski T, Hale M, Korecka M, Fitzsimmons WE, Shaw LM. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem. 2002;48:1497-1504.
46. Sanquer S, Breil M, Baron C, Dhamane D, Astier A, Lang P. Induction of inosine monophosphate dehydrogenase activity after long-term treatment with mycophenolate mofetil. Clin Pharmacol Ther. 1999;65:640-648.
47.
47. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995;60:225-232.
48.
48. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet. 1995;345:1321-1325.
49.
49. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation. 1996;61:1029-1037.
50.
50. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups [published erratum appears in Transplantation. 1997;63:618]. Transplantation. 1997;63:39-47.
51.
51. European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation. 1999;68;391-396.
52.
52. US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil in cadaveric renal transplantation. AmJ Kidney Dis. 1999;34:296-303.
53.
53. Shapiro R, JordanML, Scantlebury VP, et al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/ prednisone/mycophenolate mofetil in renal transplant recipients. Transplantation.1999;67:411-415.
54.
54. Zanker B, Schneeberger H, Rothenpieler U, et al. Mycophenolate mofetil-based, cyclosporine-free induction and maintenance immunosuppression: first-3-months analysis of efficacy and safety in two cohorts of renal allograft recipients.Transplantation. 1998;66:44-49.
55.
55. van Gelder T, Klaassen RJ, van Riemsdijk-van Overbeeke OI, Ijzermans JN, Weimar W. Mycophenolate mofetil and prednisone as maintenance treatment after kidney transplantation. Transplantation. 1997;63:1530-1531.
56.
56. Weir MR, Anderson L, Fink JC, et al. A novel approach to the treatment of chronic allograft nephropathy. Transplantation. 1997;64:1706-1710.
57.
57. Grinyo JM. Progress with cyclosporine-sparing regimens. Transplant Proc. 1999;31(suppl):11S-16S.
58.
58. Ahsan N, Hricik D, Matas A, et al. Prednisonewithdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transplantation. 1999;68:1865-1874.
59.
59. Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant. 2003;3:306-311.
60.
60. Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, Stuart FP. Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreaskidney transplantation: initial experience in 50 consecutive cases. Transplantation. 1999:67:586-593.
61.
61. Odorico JS, Pirsch JD, Knechtle SJ, D’Alessandro AM, Sollinger HW. A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation.Transplantation. 1998;66:1751-1759.
62.
62. Gruessner RW, Sutherland DE, Drangstveit MB, Wrenshall L, Humar A, Gruessner AC. Mycophenolate mofetil in pancreas transplantation. Transplantation. 1998;66:318-323.
63.
63. Gruessner RW, Sutherland DE, Drangstveit MB, West M, Gruessner AC. Mycophenolate mofetil and tacrolimus for induction and maintenance therapy after pancreas transplantation. Transplant Proc. 1998;30:518-520.
64.
64. Stegall MD, Simon M, Wachs ME, Chan L, Nolan C, Kam I. Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine. Transplantation. 1997;64:1695-1700.
65.
65. Izbicki G, Shitrit D, Aravot D, et al. Improved survival after lung transplantation in patients treated with tacrolimus/ mycophenolate mofetil as compared with cyclosporine/ azathioprine. Transplant Proc. 2002;34:3258-3259.
66.
66. Teebken OE, StruberM, HarringerW, PichlmaierMA, Haverich A. Primary immunosuppression with tacrolimus and mycophenolate mofetil versus cyclosporine and azathioprine in heart transplant recipients. Transplant Proc. 2002;34:1265-1268.
67.
67. Zuckermann A, Birsan T, Thaghavi S, et al. Benefit of mycophenolate mofetil in patients with cyclosporine A-induced nephropathy after lung transplantation. Transplant Proc. 1999;31: 1160-1161.
68.
68. Hosenpud JD, Bennett LE. Mycophenolate mofetil versus azathioprine in patients surviving the initial cardiac transplant hospitalization: an analysis of the Joint UNOS/ISHLT Thoracic Registry. Transplantation. 2001;72:1662-1665.
69.
69. Kobashigawa J, Miller L, Renlund D, et al. A randomized activecontrolled trial of mycophenolate mofetil in heart transplant recipients. MycophenolateMofetil Investigators. Transplantation. 1998;66:507-515.
70.
70. Zuckermann A, Reichenspurner H, Birsan T, et al. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg. 2003;125:891-900.
71.
71. Jain A, Kashyap R, Demetris AJ, Eghstesad B, Pokharna R, Fung JJ. A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C. Liver Transpl. 2002;8:40-46.
72.
72. Jain A, Kashyap R, Dodson F, et al. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report. Transplantation. 2001;72: 1091-1097.
73.
73. Stewart SF, Hudson M, Talbot D, Manas D, Day CP. Mycophenolate mofetil monotherapy in liver transplantation. Lancet. 2001;357:609-610.
74.
74. Smak Gregoor PJH,Hesse CJ, van Gelder T, et al. Relation of mycophenolic acid trough levels and adverse events in kidney allograft recipients. Transplant Proc. 1998;30:1192-1193.
75.
75. vanBesouwNM, van derMastBJ, SmakGregoor PJH, et al. Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels. Nephrol Dial Transplant. 1999;14:2710-2713.
76.
76. Bullingham R, Shah J, Goldblum R, Schiff M. Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients. Br J Clin Pharmacol. 1996;41:513-516.
77.
77. Seifeldin R. Drug interactions in transplantation. Clin Ther. 1995;17:1043-1061.
78.
78. Zucker K, Rosen A, Tsaroucha A, et al. Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transplant Immunol. 1997;5:225-232.
79.
79. Zucker K, Tsaroucha A, Olson L, EsquenaziV, Tzakis A, Miller J. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit. 1999;21:35-43.
80.
80. Van Gelde TR, Klupp J, Barten M, Christians U, Morris RE. Coadministration of tacrolimus and mycophenolate mofetil does not increase mycophenolic acid (MPA) exposure, but coadministration of cyclosporine and MMF inhibits the enterohepatic recirculation ofMPA, thereby decreasing its exposure. J Heart Lung Transplant. 2001;20:160-161.
81.
81. Smak Gregoor PJH, de Sevaux RG, Hené RJ, et al. Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation. 1999;68:1603-1606.
82.
82. Smak Gregoor PJH, van Gelder T, Hesse CJ, van derMast BJ, van Besouw NM, WeimarW. Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study. Nephrol DialTransplant. 1999;14:706-708.
83.
83. Shaw LM, Mick R, Nowak I, Korecka M, Brayman KL. Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function. J Clin Pharmacol. 1998;38:268-275.
84.
84. Shaw LM, Nowak I. Mycophenolic acid: measurement and relationship to pharmacologic effects. Ther Drug Monit. 1995;17:685-689.
85.
85. Meier-Kriesche HU, Shaw LM, Korecka M, Kaplan B. Pharmacokinetics of mycophenolic acid in renal insufficiency. Ther Drug Monit. 2000;22:27-30.
86.
86. Young M, Plosker GL. Mycophenolate mofetil: a pharmacoeconomicreview of its use in solid organ transplantation. Pharmacoeconomics. 2002;20:675-713.
87.
87. Venzina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibioticI. Taxonomy of the producing streptomycete and isolation of the active principle. JAntibiotics. 1975;28:721-726.
88.
88. Seghal SN, Baker H, Vezina C. Rapamycin (AY-22,989) a new antifungal antibioticII. Fermentation, isolation, and characterization. J Antibiotics. 1975;28:727-731.
89.
89. Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res. 1996;270:815-822.
90.
90. Shi Y, Frankel A, Radnayi LG, et al. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res. 1995;55:1982-1988.
91.
91. Abraham RT. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol. 1998;10:330-336.
92.
92. Vilella-Bach M, Nuzzi P, Fang Y, et al. The FKBP12-rapamycinbinding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J Biol Chem. 1999;274:4266-4272.
93.
93. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998;31:335-340.
94.
94. Lawrence JC Jr, Abraham RT. PHAS/4E-BPs as regulators of mRNA translation and cell proliferation. Trends Biochem Sci. 1997;22:345-349.
95.
95. Yatscoff RW. Pharmacokinetics of rapamycin. Transplant Proc. 1996;28:970-973.
97. Johnson EM, Zimmerman J, Duderstadt K, et al. A randomized, double-blind, placebo-controlled study of the safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in stable renal transplant recipients. Transplant Proc. 1996;28:987-987.
98.
98. Trepanier DJ, Gallant H, Legatt DF, et al. Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clin Biochem. 1998;31:345-351.
99.
99. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol. 1997;37:405-415.
100.
100. Ferron GM, Mishina EV, Zimmerman JJ, et al. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther. 1997;61:416-428.
101.
101. Yatscoff RW, Aspeslet LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug Monit. 1998;20:459-463.
102.
102. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation. 1999;67:1036-1042.
103.
103. KahanBD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation. 1998;66:1040-1046.
104.
104. Napoli KL, Kahan BD. Routine clinical monitoring of sirolimus (rapamycin) whole-blood concentrations by HPLC with ultraviolet detection. Clin Chemistry. 1996;42:1944-1944.
105.
105. Volosov A, Napoli KL, Soldin SJ. Simultaneous simple and fast quantification of three major immunosuppressants by liquid chromatography-tandem mass-spectrometry. Clin Biochem. 2001;34:285-290.
107. Kahan BD. Emerging strategies for the clinical application of rapamycin. Clin Biochem. 1998;31:341-344.
108.
108. Kahan BD, Napoli, KL. Role of therapeuticdrug monitoring of rapamycin. Transplant Proc. 1993;30:2189-2191.
109.
109. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet. 2000;356:194-202.
110.
110. MacDonald AS, for the Rapamune Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation. 2001;71:271-280.
111.
111. Hong JC, Kahan BD. Sirolimus rescue therapy for refractory rejection in renal transplantation. Transplantation. 2001;71:1579-1584.
112.
112. Mahalati K, Kahan BD. Apilot study of steroid withdrawal from kidney transplant recipients on sirolimus-cyclosporine a combination therapy. Transplant Proc. 2001;33:3232-3233.
113.
113. Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation. 2002;74:1070-1076.
114.
114. El-Sabrout R, Delaney V, Butt F, et al. Early experience using calcineurin-free protocol in recipients of high-risk cadaver renal transplants. Transplant Proc. 2002;34:1627-1628.
115.
115. Hong JC, Kahan BD. A calcineurin antagonist-free induction strategy for immunosuppression in cadaveric kidney transplant recipients at risk for delayed graft function. Transplantation. 2001;71:1320-1328.
117. Dunkelberg JC, Trotter JF, Wachs M, et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl. 2003;9:463-468.
118.
118. Gregory CR, Huie P, BillinghamME, et al. Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury. Transplantation. 1993;55:1409-1418.
119.
119. Meiser BM, Billingham ME, Morris RE. Effects of cyclosporin,FK506, and rapmycin on graft-vessel disease. Lancet. 1991;338:1297-1298.
120.
120. Gregory CR, Huang X, Pratt RE, et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation. 1995;59:655-661.
121.
121. Kahan BD. The role of rapamycin in chronic rejection prophylaxis: a theoretical consideration. Graft. 1998;1:93-96.
122.
122. King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation. 2003;75:1437-1443.
123.
123. McWilliams TJ, LevveyBJ, Russell PA, Milne DG, Snell GI. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. JHeart LungTransplant. 2003;22:210-213.
124.
124. KaplanB, Meier-Kriesche HU, Napoli KL, et al. The effects of relative timing of sirolimus and cyclosporine microemulsion formulationcoadministration on the pharmacokinetics of each agent. Clin Pharmacol Therap. 1998;63:48-53.
125.
125. Seghal SN. Rapamune (sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit. 1995;17:660-665.
126.
126. Kimball PM, Kerman RH, Kahan BD. Production of synergistic but nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine. Transplantation. 1991;51:486-490.
127.
127. Campana C, Regazzi MB, Buggia I, et al. Clinically significant drug interactions with cyclosporine. An update. Clin Pharmacokinet. 1996;30:141-179.
