Drug choices in autoimmune hepatitis: Part B - Nonsteroids

Expert Review of Gastroenterology and Hepatology

Volumn 6, Issue 5, 2012, Pages 617-635

  Czaja, Albert J ^a  

^a MAYO CLINIC   (United States)

Author keywords

autoimmune hepatitis; azathioprine; cyclosporine; mycophenolate mofetil; pharmacokinetics; rapamycin; salvage; tacrolimus

Indexed keywords

AZATHIOPRINE; CALCINEURIN INHIBITOR; CALCIUM CHANNEL BLOCKING AGENT; CARBAMAZEPINE; CORTICOSTEROID; CYCLOSPORIN; ERYTHROMYCIN; KETOCONAZOLE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; NIFEDIPINE; PHENOBARBITAL; PHENYTOIN; PREDNISOLONE; PREDNISONE; RAPAMYCIN; RIFAMPICIN; SEX HORMONE; SULFADIMIDINE; TACROLIMUS; TRIMETHOPRIM;

ABDOMINAL PAIN; ANEMIA; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; AUTOIMMUNE HEPATITIS; BONE MARROW SUPPRESSION; CELL PROLIFERATION; CHOLESTATIC HEPATITIS; CONFUSION; COUGHING; CYTOPENIA; DIABETES MELLITUS; DIARRHEA; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CHOICE; DRUG COST; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG ELIMINATION; DRUG ERUPTION; DRUG HALF LIFE; DRUG INDICATION; DRUG TREATMENT FAILURE; DYSPNEA; FATIGUE; FEVER; GASTROINTESTINAL DISEASE; GINGIVA HYPERPLASIA; GINGIVITIS; HIRSUTISM; HUMAN; HYPERLIPIDEMIA; HYPERTENSION; INDIVIDUALIZATION; INHIBITION KINETICS; LEUKOPENIA; LIVER VENOOCCLUSIVE DISEASE; LUNG ALVEOLITIS; LUNG FIBROSIS; LUNG HEMORRHAGE; MALIGNANT NEOPLASTIC DISEASE; NAUSEA; NAUSEA AND VOMITING; NEPHROTOXICITY; NEUROTOXICITY; OFF LABEL DRUG USE; OPPORTUNISTIC INFECTION; PANCREATITIS; PARADOXICAL DRUG REACTION; PARESTHESIA; PATIENT COMPLIANCE; PATIENT MONITORING; PNEUMONIA; PRURITUS; RELAPSE; REVIEW; TERATOGENICITY; UNSPECIFIED SIDE EFFECT; VOMITING;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CYCLOSPORINE; HEPATITIS, AUTOIMMUNE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MYCOPHENOLIC ACID; SIROLIMUS;

EID: 84867526442     PISSN: 17474124     EISSN: 17474132     Source Type: Journal    
DOI: 10.1586/egh.12.38     Document Type: Review

References (199)

1. Czaja AJ. Nonstandard drugs and feasible new interventions for autoimmune hepatitis. Part-I. Inflamm. Allergy Drug Targets PMID: 22563779 (2012) (Epub ahead of print).
2. Soloway RD, Summerskill WH, Baggenstoss AH et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: A controlled study of treatments and early prognosis. Gastroenterology 63(5), 820-833 (1972).
3. Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet 1(7806), 735-737 (1973).
4. Summerskill WH, Korman MG, Ammon HV, Baggenstoss AH. Prednisone for chronic active liver disease: Dose titration, standard dose, and combination with azathioprine compared. Gut 16(11), 876-883 (1975).
5. Chase WF, Winn RE, Mayes GR. Oral pulse prednisone therapy in the treatment of HBsAg negative chronic active hepatitis. Gastroenterology 83(6), 1292-1296 (1982). (Pubitemid 13235932)
6. Czaja AJ, Wang KK, Shiels MT, Katzmann JA. Oral pulse prednisone therapy after relapse of severe autoimmune chronic active hepatitis. A prospective randomized treatment trial evaluating clinical, biochemical, and lymphocyte subset responses. J. Hepatol. 17(2), 180-186 (1993). (Pubitemid 23054484)
7. Mistilis SP, Vickers CR, Darroch MH, McCarthy SW. Cyclosporin, a new treatment for autoimmune chronic active hepatitis. Med. J. Aust. 143(10), 463-465 (1985). (Pubitemid 16189821)
8. Czaja AJ. Current and future treatments of autoimmune hepatitis. Expert Rev. Gastroenterol. Hepatol. 3(3), 269-291 (2009).
9. Czaja AJ. Promising pharmacological, molecular and cellular treatments of autoimmune hepatitis. Curr. Pharm. Des. 17(29), 3120-3140 (2011).
10. Czaja AJ. Advances in the current treatment of autoimmune hepatitis. Dig. Dis. Sci. 57(8), 1996-2012 (2012).
11. Czaja AJ. Autoimmune hepatitis. Part A: Pathogenesis. Expert Rev. Gastroenterol. Hepatol. 1(1), 113-128 (2007).
12. Czaja AJ. Autoimmune hepatitis: Focusing on treatments other than steroids. Can. J. Gastroenterol. 26(9), 615-620 (2012).
13. Heneghan MA, Al-Chalabi T, McFarlane IG. Cost-effectiveness of pharmacotherapy for autoimmune hepatitis. Expert Opin. Pharmacother. 7(2), 145-156 (2006).
14. Manns MP, Czaja AJ, Gorham JD et al.; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 51(6), 2193-2213 (2010).
15. Stellon AJ, Keating JJ, Johnson PJ, McFarlane IG, Williams R. Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal. Hepatology 8(4), 781-784 (1988).
16. Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N. Engl. J. Med. 333(15), 958-963 (1995).
17. Czaja AJ, Carpenter HA. Empiric therapy of autoimmune hepatitis with mycophenolate mofetil: Comparison with conventional treatment for refractory disease. J. Clin. Gastroenterol. 39(9), 819-825 (2005). (Pubitemid 41361901)
18. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J. Hepatol. 33(3), 371-375 (2000). (Pubitemid 30663373)
19. Devlin SM, Swain MG, Urbanski SJ, Burak KW. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy. Can. J. Gastroenterol. 18(5), 321-326 (2004). (Pubitemid 38801788)
20. Chatur N, Ramji A, Bain VG et al. Transplant immunosuppressive agents in non-transplant chronic autoimmune hepatitis: The Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus. Liver Int. 25(4), 723-727 (2005). (Pubitemid 41038652)
21. Inductivo-Yu I, Adams A, Gish RG et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin. Gastroenterol. Hepatol. 5(7), 799-802 (2007). (Pubitemid 47031057)
22. Hlivko JT, Shiffman ML, Stravitz RT et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin. Gastroenterol. Hepatol. 6(9), 1036-1040 (2008).
23. Hennes EM, Oo YH, Schramm C et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am. J. Gastroenterol. 103(12), 3063-3070 (2008).
24. Wolf DC, Bojito L, Facciuto M, Lebovics E. Mycophenolate mofetil for autoimmune hepatitis: A single practice experience. Dig. Dis. Sci. 54(11), 2519-2522 (2009).
25. Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: A 5-year follow-up. J. Hepatol. 51(1), 156-160 (2009).
26. Sharzehi K, Huang MA, Schreibman IR, Brown KA. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy. Can. J. Gastroenterol. 24(10), 588-592 (2010).
27. Baven-Pronk AM, Coenraad MJ, van Buuren HR et al. The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. Aliment. Pharmacol. Ther. 34(3), 335-343 (2011).
28. Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. Mycophenolate for the treatment of autoimmune hepatitis: Prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients. J. Hepatol. 55(3), 636-646 (2011).
29. Czaja AJ. Safety issues in the management of autoimmune hepatitis. Expert Opin. Drug Saf. 7(3), 319-333 (2008). (Pubitemid 351802831)
30. Perez-Aytes A, Ledo A, Boso V et al. In utero exposure to mycophenolate mofetil: A characteristic phenotype? Am. J. Med. Genet. A 146A(1), 1-7 (2008).
31. Le Ray C, Coulomb A, Elefant E, Frydman R, Audibert F. Mycophenolate mofetil in pregnancy after renal transplantation: A case of major fetal malformations. Obstet. Gynecol. 103(5 Pt 2), 1091-1094 (2004).
32. Anderka MT, Lin AE, Abuelo DN, Mitchell AA, Rasmussen SA. Reviewing the evidence for mycophenolate mofetil as a new teratogen: Case report and review of the literature. Am. J. Med. Genet. A 149A(6), 1241-1248 (2009).
33. Klieger-Grossmann C, Chitayat D, Lavign S et al. Prenatal exposure to mycophenolate mofetil: An updated estimate. J. Obstet. Gynaecol. Can. 32(8), 794-797 (2010).
34. Lin AE, Singh KE, Strauss A, Nguyen S, Rawson K, Kimonis VE. An additional patient with mycophenolate mofetil embryopathy: Cardiac and facial analyses. Am. J. Med. Genet. A 155A(4), 748-756 (2011).
35. Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) and pregnancy. Am. J. Obstet. Gynecol. 97(3), 387-394 (1967).
36. de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodegraven AA. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am. J. Gastroenterol. 101(6), 1390-1392 (2006). (Pubitemid 43830009)
37. Chan GL, Erdmann GR, Gruber SA, Matas AJ, Canafax DM. Azathioprine metabolism: Pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients. J. Clin. Pharmacol. 30(4), 358-363 (1990). (Pubitemid 20274115)
38. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur. J. Clin. Pharmacol. 43(4), 329-339 (1992).
39. Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: Azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am. J. Gastroenterol. 91(3), 423-433 (1996). (Pubitemid 126733803)
40. Allison AC. Immunosuppressive drugs: The first 50 years and a glance forward. Immunopharmacology 47(2-3), 63-83 (2000). (Pubitemid 30394533)
41. Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: Pharmacology, efficacy, and safety. Clin. Gastroenterol. Hepatol. 2(9), 731-743 (2004). (Pubitemid 39200711)
42. Atreya I, Neurath MF. Azathioprine in inflammatory bowel disease: Improved molecular insights and resulting clinical implications. Expert Rev. Gastroenterol. Hepatol. 2(1), 23-34 (2008).
43. Thomas CW, Myhre GM, Tschumper R et al. Selective inhibition of inflammatory gene expression in activated T lymphocytes: A mechanism of immune suppression by thiopurines. J. Pharmacol. Exp. Ther. 312(2), 537-545 (2005). (Pubitemid 40189550)
44. Tiede I, Fritz G, Strand S et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J. Clin. Invest. 111(8), 1133-1145 (2003). (Pubitemid 36519931)
45. Steel AW, Mela CM, Lindsay JO, Gazzard BG, Goodier MR. Increased proportion of CD16(+) NK cells in the colonic lamina propria of inflammatory bowel disease patients, but not after azathioprine treatment. Aliment. Pharmacol. Ther. 33(1), 115-126 (2011).
46. de Boer NK, van Bodegraven AA, Jharap B, de Graaf P, Mulder CJ. Drug insight: Pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat. Clin. Pract. Gastroenterol. Hepatol. 4(12), 686-694 (2007). (Pubitemid 350199222)
47. Mudter J, Neurath MF. Apoptosis of T cells and the control of inflammatory bowel disease: Therapeutic implications. Gut 56(2), 293-303 (2007).
48. Poppe D, Tiede I, Fritz G et al. Azathioprine suppresses ezrin-radixinmoesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J. Immunol. 176(1), 640-651 (2006). (Pubitemid 43023313)
49. Cara CJ, Pena AS, Sans M et al. Reviewing the mechanism of action of thiopurine drugs: Towards a new paradigm in clinical practice. Med. Sci. Monit. 10(11), RA247-RA254 (2004). (Pubitemid 39546047)
50. Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2(5), 410-417 (2004). (Pubitemid 38561239)
51. Black AJ, McLeod HL, Capell HA et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann. Intern. Med. 129(9), 716-718 (1998). (Pubitemid 28507145)
52. Otterness D, Szumlanski C, Lennard L et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin. Pharmacol. Ther. 62(1), 60-73 (1997). (Pubitemid 27327100)
53. Weinshilboum R. Thiopurine pharmacogenetics: Clinical and molecular studies of thiopurine methyltransferase. Drug Metab. Dispos. 29(4 Pt 2), 601-605 (2001). (Pubitemid 32275544)
54. Langley PG, Underhill J, Tredger JM, Norris S, McFarlane IG. Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. J. Hepatol. 37(4), 441-447 (2002).
55. Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM. Human liver thiopurine methyltransferase pharmacogenetics: Biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics 2(4), 148-159 (1992).
56. Yates CR, Krynetski EY, Loennechen T et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126(8), 608-614 (1997). (Pubitemid 27172187)
57. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur. J. Clin. Pharmacol. 64(8), 753-767 (2008).
58. Mircheva J, Legendre C, Soria-Royer C, Thervet E, Beaune P, Kreis H. Monitoring of azathioprine-induced immunosuppression with thiopurine methyltransferase activity in kidney transplant recipients. Transplantation 60(7), 639-642 (1995).
59. Czaja AJ, Carpenter HA. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis. Dig. Dis. Sci. 51(5), 968-975 (2006). (Pubitemid 44030824)
60. Bacon BR, Treuhaft WH, Goodman AM. Azathioprine-induced pancytopenia. Occurrence in two patients with connective-tissue diseases. Arch. Intern. Med. 141(2), 223-226 (1981). (Pubitemid 11130262)
61. Maddocks JL, Lennard L, Amess J, Amos R, Thomas RM. Azathioprine and severe bone marrow depression. Lancet 1(8473), 156 (1986). (Pubitemid 16183129)
62. Ben Ari Z, Mehta A, Lennard L, Burroughs AK. Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis. J. Hepatol. 23(3), 351-354 (1995).
63. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47(2-3), 85-118 (2000). (Pubitemid 30394534)
64. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 14(Suppl. 1), S2-S8 (2005). (Pubitemid 40460509)
65. Morath C, Schwenger V, Beimler J et al. Antifibrotic actions of mycophenolic acid. Clin. Transplant. 20(Suppl. 17), 25-29 (2006). (Pubitemid 44710308)
66. Chan GL, Erdmann GR, Gruber SA et al. Pharmacokinetics of 6-thiouric acid and 6-mercaptopurine in renal allograft recipients after oral administration of azathioprine. Eur. J. Clin. Pharmacol. 36(3), 265-271 (1989). (Pubitemid 19116206)
67. el-Yazigi A, Wahab FA. Pharmacokinetics of azathioprine after repeated oral and single intravenous administration. J. Clin. Pharmacol. 33(6), 522-526 (1993). (Pubitemid 23171758)
68. Bergan S, Rugstad HE, Bentdal O, Endresen L, Stokke O. Kinetics of mercaptopurine and thioguanine nucleotides in renal transplant recipients during azathioprine treatment. Ther. Drug Monit. 16(1), 13-20 (1994). (Pubitemid 24042307)
69. Ohlman S, Albertioni F, Peterson C. Day-to-day variability in azathioprine pharmacokinetics in renal transplant recipients. Clin. Transplant. 8(3 Pt 1), 217-223 (1994). (Pubitemid 24162291)
70. Van Os EC, Zins BJ, Sandborn WJ et al. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration. Gut 39(1), 63-68 (1996). (Pubitemid 26239107)
71. Nguyen TM, Daubard M, Le Gall C, Larger M, Lachaux A, Boulieu R. Monitoring of azathioprine metabolites in pediatric patients with autoimmune hepatitis. Ther. Drug Monit. 32(4), 433-437 (2010).
72. Kwan LY, Devlin SM, Mirocha JM, Papadakis KA. Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease. Dig. Liver Dis. 40(6), 425-432 (2008).
73. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin. Pharmacokinet. 34(6), 429-455 (1998). (Pubitemid 28273453)
74. Villarroel MC, Hidalgo M, Jimeno A. Mycophenolate mofetil: An update. Drugs Today 45(7), 521-532 (2009).
75. Greanya ED, Poulin E, Partovi N, Shapiro RJ, Al-Khatib M, Ensom MH. Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen. Am. J. Health. Syst. Pharm. 69(2), 134-142 (2012).
76. Zeng L, Blair EY, Nath CE et al. Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation. Br. J. Clin. Pharmacol. 70(4), 567-579 (2010).
77. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin. Pharmacokinet. 46(1), 13-58 (2007). (Pubitemid 46091591)
78. Filler G. Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation. Pediatr. Transplant. 10(6), 707-711 (2006). (Pubitemid 44186293)
79. Shaw LM, Korecka M, DeNofrio D, Brayman KL. Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients. Clin. Biochem. 34(1), 17-22 (2001). (Pubitemid 32178501)
80. Neumann I, Fuhrmann H, Kanzler M et al. Pharmacokinetics of enteric-coated mycophenolate sodium: Comparative study in patients with autoimmune disease and renal allograft. Expert Opin. Pharmacother. 9(6), 879-886 (2008). (Pubitemid 351593736)
81. Manzia TM, De Liguori Carino N, Orlando G et al. Use of mycophenolate mofetil in liver transplantation: A literature review. Transplant. Proc. 37(6), 2616-2617 (2005). (Pubitemid 41354690)
82. Arns W, Cibrik DM, Walker RG et al. Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: Review of the literature. Transplantation 82(8), 1004-1012 (2006). (Pubitemid 44632114)
83. Shaw LM, Kaplan B, DeNofrio D, Korecka M, Brayman KL. Pharmacokinetics and concentration-control investigations of mycophenolic acid in adults after transplantation. Ther. Drug Monit. 22(1), 14-19 (2000). (Pubitemid 30083089)
84. Kim H, Long-Boyle J, Rydholm N et al. Population pharmacokinetics of unbound mycophenolic acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation. J. Clin. Pharmacol. doi:10.1177/0091270011422814 (2011) (Epub ahead of print).
85. de Winter BC, Monchaud C, Prémaud A et al. Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients. Clin. Pharmacokinet. 51(1), 29-39 (2012).
86. Filler G, Bendrick-Peart J, Christians U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther. Drug Monit. 30(2), 138-142 (2008). (Pubitemid 351521639)
87. Barau C, Barrail-Tran A, Hemerziu B et al. Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients. Liver Transpl. 17(10), 1152-1158 (2011).
88. Park SI, Felipe CR, Pinheiro-Machado PG et al. Tacrolimus pharmacokinetic drug interactions: Effect of prednisone, mycophenolic acid or sirolimus. Fundam. Clin. Pharmacol. 23(1), 137-145 (2009).
89. Tornatore KM, Sudchada P, Dole K et al. Mycophenolic acid pharmacokinetics during maintenance immunosuppression in African-American and Caucasian renal transplant recipients. J. Clin. Pharmacol. 51(8), 1213-1222 (2011).
90. Betonico GN, Abudd-Filho M, Goloni-Bertollo EM, Pavarino-Bertelli E. Pharmacogenetics of mycophenolate mofetil: A promising different approach to tailoring immunosuppression? J. Nephrol. 21(4), 503-509 (2008).
91. Lévesque E, Benoit-Biancamano MO, Delage R, Couture F, Guillemette C. Pharmacokinetics of mycophenolate mofetil and its glucuronide metabolites in healthy volunteers. Pharmacogenomics 9(7), 869-879 (2008).
92. Cantarovich M, Brown NW, Ensom MH et al. Mycophenolate monitoring in liver, thoracic, pancreas, and small bowel transplantation: A consensus report. Transplant. Rev. (Orlando). 25(2), 65-77 (2011).
93. Manns MP, Woynarowski M, Kreisel W et al.; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 139(4), 1198-1206 (2010).
94. Strassburg CP, Manns MP. Therapy of autoimmune hepatitis. Best Pract. Res. Clin. Gastroenterol. 25(6), 673-687 (2011).
95. Kanzler S, Löhr H, Gerken G, Galle PR, Lohse AW. Long-term management and prognosis of autoimmune hepatitis (AIH): A single center experience. Z. Gastroenterol. 39(5), 339-341, 344-348 (2001).
96. Heneghan MA, Allan ML, Bornstein JD, Muir AJ, Tendler DA. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J. Hepatol. 45(4), 584-591 (2006). (Pubitemid 44307381)
97. Wang KK, Czaja AJ, Beaver SJ, Go VL. Extrahepatic malignancy following long-term immunosuppressive therapy of severe hepatitis B surface antigen-negative chronic active hepatitis. Hepatology 10(1), 39-43 (1989). (Pubitemid 19170001)
98. Werner M, Almer S, Prytz H et al. Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long-term follow-up in 473 Swedish patients. J. Hepatol. 50(2), 388-393 (2009).
99. Leung J, Dowling L, Obadan I et al. Risk of non-melanoma skin cancer in autoimmune hepatitis. Dig. Dis. Sci. 55(11), 3218-3223 (2010).
100. DePinho RA, Goldberg CS, Lefkowitch JH. Azathioprine and the liver. Evidence favoring idiosyncratic, mixed cholestatichepatocellular injury in humans. Gastroenterology 86(1), 162-165 (1984). (Pubitemid 14177332)
101. Lee AU, Farrell GC. Mechanism of azathioprine-induced injury to hepatocytes: Roles of glutathione depletion and mitochondrial injury. J. Hepatol. 35(6), 756-764 (2001). (Pubitemid 34717667)
102. Eland IA, van Puijenbroek EP, Sturkenboom MJ, Wilson JH, Stricker BH. Drugassociated acute pancreatitis: Twenty-one years of spontaneous reporting in The Netherlands. Am. J. Gastroenterol. 94(9), 2417-2422 (1999). (Pubitemid 29420667)
103. Wright SH, Czaja AJ, Katz RS, Soloway RD. Systemic mycosis complicating high dose corticosteroid treatment of chronic active liver disease. Am. J. Gastroenterol. 74(5), 428-432 (1980). (Pubitemid 11191018)
104. Ziegler TR, Fernández-Estívariz C, Gu LH, Fried MW, Leader LM. Severe villus atrophy and chronic malabsorption induced by azathioprine. Gastroenterology 124(7), 1950-1957 (2003). (Pubitemid 36666790)
105. Read AE, Wiesner RH, LaBrecque DR et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann. Intern. Med. 104(5), 651-655 (1986). (Pubitemid 16114559)
106. Katzka DA, Saul SH, Jorkasky D, Sigal H, Reynolds JC, Soloway RD. Azathioprine and hepatic venocclusive disease in renal transplant patients. Gastroenterology 90(2), 446-454 (1986). (Pubitemid 16136691)
107. Vernier-Massouille G, Cosnes J, Lemann M et al. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 56(10), 1404-1409 (2007). (Pubitemid 47517834)
108. Bajaj JS, Saeian K, Varma RR et al. Increased rates of early adverse reaction to azathioprine in patients with Crohn's disease compared to autoimmune hepatitis: A tertiary referral center experience. Am. J. Gastroenterol. 100(5), 1121-1125 (2005). (Pubitemid 40769051)
109. Czaja AJ. Mycophenolate mofetil to the rescue in autoimmune hepatitis: A fresh sprout on the decision tree. J. Hepatol. 51(1), 8-10 (2009).
110. Pfitzmann R, Klupp J, Langrehr JM et al. Mycophenolatemofetil for immunosuppression after liver transplantation: A follow-up study of 191 patients. Transplantation 76(1), 130-136 (2003). (Pubitemid 36877126)
111. Seikaly MG. Mycophenolate mofetil-is it worth the cost? The in-favor opinion. Pediatr. Transplant. 3(1), 79-82 (1999). (Pubitemid 29234297)
112. Hyams JS, Ballow M, Leichtner AM. Cyclosporine treatment of autoimmune chronic active hepatitis. Gastroenterology 93(4), 890-893 (1987). (Pubitemid 17156017)
113. Person JL, McHutchison JG, Fong TL, Redeker AG. A case of cyclosporinesensitive, steroid-resistant, autoimmune chronic active hepatitis. J. Clin. Gastroenterol. 17(4), 317-320 (1993). (Pubitemid 23360387)
114. Sherman KE, Narkewicz M, Pinto PC. Cyclosporine in the management of corticosteroid-resistant type I autoimmune chronic active hepatitis. J. Hepatol. 21(6), 1040-1047 (1994).
115. Jackson LD, Song E. Cyclosporin in the treatment of corticosteroid resistant autoimmune chronic active hepatitis. Gut 36(3), 459-461 (1995).
116. Debray D, Maggiore G, Girardet JP, Mallet E, Bernard O. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis. J. Pediatr. 135(1), 111-114 (1999). (Pubitemid 30180574)
117. Fernandes NF, Redeker AG, Vierling JM, Villamil FG, Fong TL. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am. J. Gastroenterol. 94(1), 241-248 (1999). (Pubitemid 29063476)
118. Alvarez F, Ciocca M, Cañero-Velasco C et al. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J. Hepatol. 30(2), 222-227 (1999). (Pubitemid 29071183)
119. Malekzadeh R, Nasseri-Moghaddam S, Kaviani MJ, Taheri H, Kamalian N, Sotoudeh M. Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis. Dig. Dis. Sci. 46(6), 1321-1327 (2001). (Pubitemid 32523281)
120. Cuarterolo M, Ciocca M, Velasco CC et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J. Pediatr. Gastroenterol. Nutr. 43(5), 635-639 (2006). (Pubitemid 44863691)
121. Van Thiel DH, Wright H, Carroll P et al. Tacrolimus: A potential new treatment for autoimmune chronic active hepatitis: Results of an open-label preliminary trial. Am. J. Gastroenterol. 90(5), 771-776 (1995).
122. Aqel BA, Machicao V, Rosser B, Satyanarayana R, Harnois DM, Dickson RC. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J. Clin. Gastroenterol. 38(9), 805-809 (2004). (Pubitemid 39274185)
123. Larsen FS, Vainer B, Eefsen M, Bjerring PN, Adel Hansen B. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis. World J. Gastroenterol. 13(23), 3232-3236 (2007). (Pubitemid 47064587)
124. Hurtova M, Duclos-Vallée JC, Johanet C et al. Successful tacrolimus therapy for a severe recurrence of type 1 autoimmune hepatitis in a liver graft recipient. Liver Transpl. 7(6), 556-558 (2001). (Pubitemid 32547275)
125. Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 46(4), 1138-1145 (2007). (Pubitemid 350144778)
126. Martínez-Martínez S, Redondo JM. Inhibitors of the calcineurin/NFAT pathway. Curr. Med. Chem. 11(8), 997-1007 (2004). (Pubitemid 38425927)
127. Serfling E, Berberich-Siebelt F, Avots A et al. NFAT and NF-kappaB factors-the distant relatives. Int. J. Biochem. Cell Biol. 36(7), 1166-1170 (2004). (Pubitemid 38515658)
128. Macian F. NFAT proteins: key regulators of T-cell development and function. Nat. Rev. Immunol. 5(6), 472-484 (2005). (Pubitemid 40835035)
129. Turner JD, Thomas AP, Reeves JP, Hantash BM. Calcineurin activation by slow calcium release from intracellular stores suppresses protein kinase C regulation of L-type calcium channels in L6 cells. Cell Calcium 46(4), 242-247 (2009).
130. Akhlaghi F, Trull AK. Distribution of cyclosporin in organ transplant recipients. Clin. Pharmacokinet. 41(9), 615-637 (2002).
131. Galat A, Bua J. Molecular aspects of cyclophilins mediating therapeutic actions of their ligands. Cell. Mol. Life Sci. 67(20), 3467-3488 (2010).
132. Alvarez-Arroyo MV, Yagüe S, Wenger RM et al. Cyclophilin-mediated pathways in the effect of cyclosporin A on endothelial cells: Role of vascular endothelial growth factor. Circ. Res. 91(3), 202-209 (2002). (Pubitemid 34875674)
133. Pissaia A Jr, Aoudjehane L, Ben Othman S et al. Cyclosporine inhibits profibrotic effects of interleukin-4 and transforming growth factor on human intrahepatic fibroblasts cultured in vitro. Transplant. Proc. 42(10), 4343-4346 (2010).
134. Holländer GA, Bierer BE, Burakoff SJ. Molecular and biological actions of cyclosporin A and FK506 on T cell development and function. Transfus. Sci. 15(3), 207-220 (1994). (Pubitemid 24267835)
135. Hess AD, Fischer AC, Horwitz LR, Laulis MK. Cyclosporine-induced autoimmunity: Critical role of autoregulation in the prevention of major histocompatibility class II-dependent autoaggression. Transplant. Proc. 25(5), 2811-2813 (1993). (Pubitemid 23314248)
136. Hooks MA. Tacrolimus, a new immunosuppressant-a review of the literature. Ann. Pharmacother. 28(4), 501-511 (1994). (Pubitemid 24123768)
137. Iwasaki K. Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab. Pharmacokinet. 22(5), 328-335 (2007).
138. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66(4), 807-815 (1991). (Pubitemid 121001714)
139. Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341(6244), 755-757 (1989). (Pubitemid 19260892)
140. Wang T, Donahoe PK, Zervos AS. Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12. Science 265(5172), 674-676 (1994). (Pubitemid 24268280)
141. Jørgensen KA, Koefoed-Nielsen PB, Karamperis N. Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus. Scand. J. Immunol. 57(2), 93-98 (2003). (Pubitemid 36232875)
142. de Groen PC. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin. Proc. 63(10), 1012-1021 (1988). (Pubitemid 18261527)
143. de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RA. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N. Engl. J. Med. 317(14), 861-866 (1987).
144. Canafax DM, Ascher NL. Cyclosporine immunosuppression. Clin. Pharm. 2(6), 515-524 (1983). (Pubitemid 14247921)
145. Vine W, Bowers LD. Cyclosporine: Structure, pharmacokinetics, and therapeutic drug monitoring. Crit. Rev. Clin. Lab. Sci. 25(4), 275-311 (1987).
146. Ozbay A, Karamperis N, Jørgensen KA. A review of the immunosuppressive activity of cyclosporine metabolites: New insights into an old issue. Curr. Clin. Pharmacol. 2(3), 244-248 (2007). (Pubitemid 47520963)
147. Freeman DJ. Pharmacology and pharmacokinetics of cyclosporine. Clin. Biochem. 24(1), 9-14 (1991).
148. Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol. Ther. 112(1), 184-198 (2006). (Pubitemid 44301492)
149. Christians U, Strom T, Zhang YL et al. Active drug transport of immunosuppressants: New insights for pharmacokinetics and pharmacodynamics. Ther. Drug Monit. 28(1), 39-44 (2006). (Pubitemid 44391692)
150. Noble S, Markham A. Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral). Drugs 50(5), 924-941 (1995).
151. Venkataramanan R, Swaminathan A, Prasad T et al. Clinical pharmacokinetics of tacrolimus. Clin. Pharmacokinet. 29(6), 404-430 (1995). (Pubitemid 26004179)
152. Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: A new immunosuppressive agent. Am. J. Health. Syst. Pharm. 52(14), 1521-1535 (1995).
153. Aumente Rubio MD, Arizón del Prado JM, López Malo de Molina MD et al. Clinical pharmacokinetics of tacrolimus in heart transplantation: New strategies of monitoring. Transplant. Proc. 35(5), 1988-1991 (2003). (Pubitemid 37093787)
154. Wojnowski L, Kamdem LK. Clinical implications of CYP3A polymorphisms. Expert Opin. Drug Metab. Toxicol. 2(2), 171-182 (2006). (Pubitemid 46372363)
155. Utecht KN, Hiles JJ, Kolesar J. Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors. Am. J. Health. Syst. Pharm. 63(23), 2340-2348 (2006). (Pubitemid 44851775)
156. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin. Pharmacokinet. 49(3), 141-175 (2010).
157. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single
158. Baciewicz AM, Baciewicz FA Jr. Cyclosporine pharmacokinetic drug interactions. Am. J. Surg. 157(2), 264-271 (1989). (Pubitemid 19061952)
159. Dirks NL, Huth B, Yates CR, Meibohm B. Pharmacokinetics of immunosuppressants: A perspective on ethnic differences. Int. J. Clin. Pharmacol. Ther. 42(12), 701-718 (2004). (Pubitemid 39625130)
160. Kuypers DR. Immunosuppressive drug monitoring-what to use in clinical practice today to improve renal graft outcome. Transpl. Int. 18(2), 140-150 (2005). (Pubitemid 41743303)
161. Winkler M, Christians U. A risk-benefit assessment of tacrolimus in transplantation. Drug Saf. 12(5), 348-357 (1995).
162. Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 54(6), 925-975 (1997). (Pubitemid 27526900)
163. Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: A further update of its use in the management of organ transplantation. Drugs 63(12), 1247-1297 (2003). (Pubitemid 36750952)
164. Faulds D, Goa KL, Benfield P. Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 45(6), 953-1040 (1993). (Pubitemid 23219075)
165. Bechstein WO. Neurotoxicity of calcineurin inhibitors: Impact and clinical management. Transpl. Int. 13(5), 313-326 (2000).
166. Serkova NJ, Christians U, Benet LZ. Biochemical mechanisms of cyclosporine neurotoxicity. Mol. Interv. 4(2), 97-107 (2004). (Pubitemid 38584972)
167. Wu Q, Marescaux C, Wolff V et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur. Neurol. 64(3), 169-177 (2010).
168. Toledo Perdomo K, Navarro Cabello MD, Pérez Sáez MJ, Ramos Pérez MJ, Agüera Morales ML, Aljama García P. Reversible acute encephalopathy with mutism, induced by calcineurin inhibitors after renal transplantation. J. Nephrol. 25(5), 839-842 (2012).
169. Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig. Dis. Sci. 57(9), 2248-2266 (2012).
170. Liberal R, Longhi MS, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis after liver transplantation. Clin. Gastroenterol. Hepatol. 10(4), 346-353 (2012).
171. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 18(16), 1926-1945 (2004). (Pubitemid 39071573)
172. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 124(3), 471-484 (2006). (Pubitemid 43199434)
173. Yellen P, Saqcena M, Salloum D et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 10(22), 3948-3956 (2011).
174. Kerkar N, Dugan C, Rumbo C et al. Rapamycin successfully treats posttransplant autoimmune hepatitis. Am. J. Transplant. 5(5), 1085-1089 (2005). (Pubitemid 40571258)
175. Marzec M, Liu X, Wysocka M, Rook AH, Odum N, Wasik MA. Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells. PLoS ONE 6(9), e24849 (2011).
176. Wagner F, Henningsen B, Lederer C et al. Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients. Eur. J. Cancer 48(15), 2442-2450 (2012).
177. Choi SJ, You HS, Chung SY. Rapamycininduced cytotoxic signal transduction pathway. Transplant. Proc. 40(8), 2737-2739 (2008).
178. Zhang Y, Zhang JW, Lv GY, Xie SL, Wang GY. Effects of STAT3 gene silencing and rapamycin on apoptosis in hepatocarcinoma cells. Int. J. Med. Sci. 9(3), 216-224 (2012).
179. Nikolaeva N, Bemelman FJ, Yong SL, van Lier RA, ten Berge IJ. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation 81(3), 445-454 (2006).
180. Strauss L, Whiteside TL, Knights A, Bergmann C, Knuth A, Zippelius A. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J. Immunol. 178(1), 320-329 (2007). (Pubitemid 46033615)
181. MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin. Ther. 22(Suppl. B), B101-B121 (2000). (Pubitemid 30306050)
182. McAlister VC, Mahalati K, Peltekian KM, Fraser A, MacDonald AS. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther. Drug Monit. 24(3), 346-350 (2002). (Pubitemid 34553198)
183. Bai S, Stepkowski SM, Kahan BD, Brunner LJ. Metabolic interaction between cyclosporine and sirolimus. Transplantation 77(10), 1507-1512 (2004). (Pubitemid 38703029)
184. Le Meur Y, Djebli N, Szelag JC et al. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clin. Pharmacol. Ther. 80(1), 51-60 (2006). (Pubitemid 43946845)
185. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: From retrospective analyses to prospective studies. Transplant. Proc. 39(7), 2142-2144 (2007). (Pubitemid 47418130)
186. Schubert M, Venkataramanan R, Holt DW et al. Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am. J. Transplant. 4(5), 767-773 (2004). (Pubitemid 38637576)
187. Reichen J, Stickel F, Bhattacharya I, Matschke K, Maller E, Korth-Bradley J. Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts. Eur. J. Clin. Pharmacol. 68(5), 589-597 (2012).
188. Cattaneo D, Merlini S, Pellegrino M et al. Therapeutic drug monitoring of sirolimus: Effect of concomitant immunosuppressive therapy and optimization of drug dosing. Am. J. Transplant. 4(8), 1345-1351 (2004). (Pubitemid 39013583)
189. Kovarik JM, Curtis JJ, Hricik DE, Pescovitz MD, Scantlebury V, Vasquez A. Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus. Transplant. Proc. 38(10), 3456-3458 (2006). (Pubitemid 44908476)
190. Ware N, MacPhee IA. Current progress in pharmacogenetics and individualized immunosuppressive drug dosing in organ transplantation. Curr. Opin. Mol. Ther. 12(3), 270-283 (2010).
191. Pham PT, Pham PC, Danovitch GM et al. Sirolimus-associated pulmonary toxicity. Transplantation 77(8), 1215-1220 (2004). (Pubitemid 38580300)
192. Roberts RJ, Wells AC, Unitt E et al. Sirolimus-induced pneumonitis following liver transplantation. Liver Transpl. 13(6), 853-856 (2007). (Pubitemid 46939439)
193. Veroux M, Tallarita T, Corona D, D'Assoro A, Gurrieri C, Veroux P. Sirolimus in solid organ transplantation: Current therapies and new frontiers. Immunotherapy 3(12), 1487-1497 (2011).
194. Villamil F, Pollard S. C2 monitoring of cyclosporine in de novo liver transplant recipients: The clinician's perspective. Liver Transpl. 10(5), 577-583 (2004). (Pubitemid 38628217)
195. de Jonge H, Naesens M, Kuypers DR. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: Possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther. Drug Monit. 31(4), 416-435 (2009).
196. Cattaneo D, Perico N, Remuzzi G. From pharmacokinetics to pharmacogenomics: A new approach to tailor immunosuppressive therapy. Am. J. Transplant. 4(3), 299-310 (2004). (Pubitemid 38282284)
197. van Rossum HH, de Fijter JW, van Pelt J. Pharmacodynamic monitoring of calcineurin inhibition therapy: Principles, performance, and perspectives. Ther. Drug Monit. 32(1), 3-10 (2010).
198. Czaja AJ. Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig. Dis. Sci. 55(10), 2712-2726 (2010).
199. Czaja AJ. Nonstandard drugs and feasible new interventions for autoimmune hepatitis. Part-II. Inflamm. Allergy. Drug. Targets PMID:22563780 (2012) (Epub ahead of print).