Leflunomide and malononitrilamides

American Journal of the Medical Sciences

Volumn 313, Issue 5, 1997, Pages 289-301

  Silva Jr , Helio Tedesco ^a,b   Morris, Randall Ellis ^b  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Autoimmune diseases; Immunosuppression; Leflunomide; Malononitrilamides; Transplantation

Indexed keywords

CYCLOSPORIN; DIHYDROOROTATE DEHYDROGENASE; LEFLUNOMIDE; MALONONITRILE; TERIFLUNOMIDE;

ALLOTRANSPLANTATION; ALOPECIA; ARTICLE; AUTOIMMUNITY; CLINICAL TRIAL; DRUG ABSORPTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG MECHANISM; GASTROINTESTINAL TOXICITY; GRAFT SURVIVAL; HUMAN; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; NONHUMAN; ORAL DRUG ADMINISTRATION; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; RASH; RHEUMATOID ARTHRITIS; THROMBOCYTOPENIA; XENOTRANSPLANTATION;

EID: 0030987746     PISSN: 00029629     EISSN: None     Source Type: Journal    
DOI: 10.1097/00000441-199705000-00008     Document Type: Article

References (101)

1. Bartlett RR, Campion G, Musikic P, Schleyerbach R. Loflunomide: A novel immunomodulating drug. In: Furst AJLDE, ed. Non-steroidal anti-inflammatory drug: Mechanisms and clinical uses, 2nd ed. New York, Marcel Dekker, Inc., 1994;349-66.
2. Axton CA, Billinghan MEJ, Bishop PM, Gallegher PT, Hicks TA, Kitchen EA, et al. Novel immunosuppressive butenamides. J Chem Soc Perkin Trans. 1992;1:2203-13.
3. Williamson RA, Yea CM, Robinson PA, Curnock A, Gadher S, Hambleton AB, et al. Dihydroorotate dehydrigenase, a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem. 1995;270(38):22467-72.
4. Kuo EA, Hambleton P, Kay DP, Evans PL, Matharu SS, Little E, et al. Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-Cyano-3-cyclopropyl-3-hydroxy-N-[3′-methyl-4′(trifluoromethyl) phenyl]propenamide and related compounds. J Med Chem. 1996;39:4608-21.
5. Shimokado K, Umezawa K, Ogata J. Tyrosine kinase inhibitors inhibit multiple steps of the cell cycle of vascular smooth muscle cells. Exp Cell Res. 1995;220:266-73.
6. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61:203-12.
7. Xu X, Williams JW, Bremer KG, Finnegan A, Chong AS-F. Inhibition of protein tyrosine kinase phosphorilation in T cells by a novel immunosuppressive agent, Leflunomide. J Biol Chem. 1995;270(21):12398-403.
8. Nikcevich DA, Finnegan A, Chong AS-F, Williams JW, Bremer EG. Inhibition of interleukin 2 (IL-2)-stimulated tyrosine kinase activity by leflunomide. Agents and Actions. 1994;41:C279-82.
9. Xu X, Williams JW, Gong H, Finnegan A, Chong AS-F. Two activities of the immunosuppressive metabolite leflunomide, A77 1726: Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochemical Pharmacology. 1996;52:527-34.
10. Jone ME. Pyrimidine nucleotides biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis. Annu Rev Biochem. 1980;49:253-6.
11. Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 3rd ed. Philadelphia, John Wiley & Sons, Inc., 1992:530-71.
12. Marijnen YMT, Korte DD, Haverkort WA, Brejen EJSd, Gennip AHv, Roos D. Studies on the incorporation of precursors into purine and pyrimidine nucleotides via ''de novo" and "salvage" pathways in normal lymphocytes and lymphoblastic cell-line cells. Biochim Biophys Acta. 1989;1012(2):148-55.
13. Fairbanks LD, Bofill M, Ruckeman K, Simmonds HA. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. J Biol Chem. 1995;270(50):29682-9.
14. Simmonds HA. Diagnosis and treatment of inborn errors of purine and pyrimidine metabolism: An overview. Adv Exp Med Biol. 1994;370:1-6.
15. Peters GJ, Veerkamp JH. Purine and pyrimidine metabolism in the peripheral blood lymphocytes. Int J Biochem. 1983;15:115-23.
16. Barankiewicz J, Cohen A. Purine nucleotide metabolism in phytohemaglutinin-induced human T lymphocytes. Arch Biochem Biophys. 1987;258:167-75.
17. Weber G. Biochemical strategy of cancer cells and design of chemotherapy: G.H.A. Clowes memorial lecture. Cancer Res. 1983;43:3466-92.
18. Dayton JS, Turka LA, Thompson CB, Mitchell BS. Comparison of the effects of mizoribine with those of azathioprine, 6-mercaptopurine, and mycophenolic acid on T lymphocyte proliferation and purine ribonucleotide metabolism. Mol Pharmacol. 1992;41:671-6.
19. Peters G, Schwartsmann G, Nadal J, Laurence EJ, van Groeningen CL, van der Vijgh WJF, et al. In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Res. 1990;50:4644-9.
20. Allison AC, Eugui EM. Inhibitors of de novo purine and pyrimidine synthesis as immunosuppressive drugs. Transplant Proc. 1993;25(3[suppl 2]):8-18.
21. Angermüller S, Löffler M. Localization of dihydroorotate oxidase in myocardium and kidney cortex of the rat. Histochemistry. 1995;103:287-92.
22. Greene S, Watanabe K, Braatz-Trulson J, Lou L. Inhibition of dihydrooratate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol. 1995; 50(6):861-7.
23. Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry. 1996;35:1270-3.
24. Cherwinski HM, McCarley D, Schatzman R, Devens B, Ransom JT. The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism. J Pharmacol Exp Ther. 1995;272:460-8.
25. Morris RE, Huang X, Cao W, Zheng B, Shorthouse RA. Leflunomide (HWA 486) and its analog suppress T- and B-cell proliferation in vitro, acute rejection, ongoing rejection, and antidonor antibody synthesis in mouse, rat, and cynomolgus monkey transplant recipients as well as arterial intimal thickening after balloon catheter injury. Transplant Proc. 1995;27(1):445-7.
26. Mattar T, Kochhar K, Bartlett R, Bremer EG, Finnegan A. Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Lett 1993; 334(2):161-4.
27. Cao WW, Kao PN, Chao AC, Gardner P, Ng ABJ, Morris RE. Mechanism of the anti-proliferative action of Leflunomide. A771726, the active metabolite of leflunomide, does not block T cell receptor-mediated signal transduction but its antiproliferative effects are antagonized by pyrimidine nucleosides. J Heart Lung Transplant. 1995;14(6):1016-30.
28. Nair RV, Cao W, Morris RE. Inhibition of smooth muscle cell proliferation in vitro by leflunomide, a now immunosuppressant, is antagonized by uridine. Immunol Lett. 1995; 47:171-4.
29. Siemasko KF, Chong ASF, Williams JW, Bremmer EG, Finnegan A. Regulation of B cell function by the immunosuppressive agent Leflunomide. Transplantation. 1996; 61(4):635-42.
30. Nair RV, Cao W, Morris RE. The antiproliferative effect of leflunomide on vascular smooth muscle cells in vitro is mediated by selective inhibition of pyrimidine biosynthesis. Transplant Proc. 1996;28(6):3081.
31. Chong AS-F, Finnegan A, Jiang X, Gebel H, Sankary HN, Forster P, et al. Leflunomide, a novel immunosupressive agent: The mechanism of inhibition of T cell proliferation. Transplantation. 1993;55(6):1361-6.
32. Zielinski T, Muller H-J, Bartlett RR. Effects of loflunomide (HWA 486) on expression of lymphocyte activation markers. Agents and Actions. 1993;38:80-2.
33. Lang H, Wagner H, Heeg K. Differential effects of the immunosuppressive agents cyclosporine and leflunomide in vivo. Transplantation. 1995;59(3):382-9.
34. Cao WW, Kao PN, Aoki Y, Xu JC, Shorthouse R, Morris RE. A novel mechanism of action of the immunomodulatory drug. leflunomide: Augmentation of the immunosuppressive cytokine, TGFbl, and suppression of the immunostimulatory cytokine, IL-2. Transplant Proc. 1996;28(6):3079-80.
35. Palladino MA, Morris RE, Starnes HE, Levinson AD. The transforming growth factor-betas. A new family of immunoregulatory molecules. Ann N Y Acad Sci. 1990;593: 181-7.
36. Bartlett R. Immunopharmacological profile of HWA 486, a novel isoxazol derivative - II. In vivo immunomodulating effects differ from those of cyclosphosphamide, prednisone, or cyclosporin A. Int J Immunopharmacol. 1986;8(2):199-204.
37. Cherwinski HM, Webster DJ, Ransom JT. The immunosuppressive/anti-inflammatory molecule leflunomide causes apoptosis in mitogen stimulated human T cells. 9th International Congress of Immunology, San Francisco, CA, 1995.
38. 1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Gene & Development. 1996;10:934-47.
39. Sherr CJ. G1 phase progression: Cycling on cue. Cell. 1994; 79:551-5.
40. Allison AC, Kowaslski WJ, Muller CJ, Waters RV, Eugui EM. Mycophenolic acid and brequinar, inhibitors of purine and pyrimidine synthesis, block the glycosilation of adhesion molecules. Transplant Proc. 1993;25(3[suppl 2]):67-70.
41. Dimitrijevic M, Bartlett RR. Loflunomide, a novel immunomodulating drug inhibits homotypic adhesion of mononuclear cells in rheumatoid arthritis. Transplant Proc. 1996;28(6):3086-7.
42. Bartlett RR, Mattar T, Weithmann U, Anagnostopoulos H, Popovic S, Schleyerbach R. Leflunomide (HWA 486): A novel immunorestoring drug. Therapeutic approaches to inflammatory diseases. In: Lewis AJ, Doherty NS, Ackerman NR, eds. Proceedings of the Fourth International Conference of the Inflammation Research Association, October 23-27, Whitehaven, PA. Elsevier; 1988:215-228.
43. Weithmann KU, Jeske S, Schlotte V. Effect of leflunomide on constitutive and inducible pathways of cellular eicosanoid generation. Agent Actions. 1994;41:164-70.
44. Kurrle R, Bartlett R, Ruuth E, Laufler L, Schorlemmer HU. Malononitrilamides inhibit T- and B-cell responsiveness. Transplant Proc. 1996;28(6):3053-6.
45. Silva HT, Cao W, Shorthouse R, Morris RE. Mechanism of action of leflunomide: in vivo administration of uridine reverses its inhibition of lymphocyte proliferation. Transplant Proc. 1996;28(6):3082-4.
46. Silva HT, Cao W, Shorthouse R, Löfller M, Morris RE. In vitro and in vivo effects of leflunomide (LFM), brequinar (BQR) and cyclosporine (CsA) on pyrimidine biosynthesis. Transplant Proc. 1996;29.
47. Glant TT, Mikecz K, Brennan F, Negroiu G, Bartlett R. Suppression of autoimmune responses and inflammatory events by leflunomide in an animal model for rheumatoid arthritis. Agents and Actions. 1994;41:C267-70.
48. Bartlett RB, Dimitrijevic M, Mattar T, et al. Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. Agents and Actions. 1991;32(1/2):10-21.
49. Popovic S, Bartlett R. Disease modifying activity of HWA 486 on the development of SLE in MRL/1-mice. Agents and Actions. 1986;19(5/6):313-4.
50. Popovic S, Bartlett R. The use of murine chronic graft vs. host (CGVH) disease, a model for systemic lupus erythematosus (SLE), for drug discovery. Agents and Actions. 1987;21(3/4):284-6.
51. Vidic-Dankovic B, Kosec D, Damjanovic M, Apostolski S, Isakovic K, Bartlett RR. Leflunomide prevents the development of experimentally induced myasthenia gravis. Int J Immunopharmacol. 1995;17(4):273-81.
52. Thoenes G, Sitter T, Langer K, Bartlett R, Schleyerbach R. Leflunomide (HWA 486) inhibits experimental autoimmune tubulointerstitial nephritis in rats. Int J Immunopharmacol. 1989;11(8):921-9.
53. Ogawa T, Inazu M, Gotoh K, Inoue T, Hayashi S. Therapeutic effects of leflunomide, a new antirheumatic drug, on glomerulonephritis induced by antibasement membrane antibody in rats. Clin Immunol Immunopathol. 1991;61: 103-18.
54. Robertson SM, Lang LS. Leflunomide: Inhibition of S-antigen induced autoimmune uveitis in Lewis rats. Agents and Action. 1994;42:167-72.
55. Williams JW, Xao F, Forster P, Clardy C, McChesney L, Sankary H, et al. Leflunomide in experimental transplantation. Transplantation. 1994;57(8):1223-31.
56. Lin Y, Sobis H, Vandeputte M, Waer M. Mechanism of leflunomide-induced prevention of xenoantibody formation and xenograft rejection in the hamster to rat heart transplantation model. Transplant Proc. 1995;27(1):305-6.
57. Lucien J, Marath A, Rayat G, Thliveris J, Koshal A, Yatscoff R. Efficacy of leflunomide to reduce xenoantibody titers in vivo: An evaluation of prolongation of discordant xenograft survival. Transplant Proc. 1996;28(2):704-7.
58. Cheung A, Billingham M, Zheng B, Silva H, Shorthouse R, Morris RE. Leflunomide abrogates hyperacute heart allograft rejection in presensitized rats. Transplant Proc. 1996;29.
59. Kasaian MT, Ikematsu H Casali P. Identification and analysis of a novel human surface CD5-B lymphocyte subset producing natural antibodies. J Immunol. 1992;148(9): 2690-702.
60. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993;261(5119):355-8.
61. Lin Y, Vandeputte M, Waer M. Effect of leflunomide on T-independent xenoantibody formation in rats receiving hamster heart xenograft. Transplant Proc. 1996;28(2):952.
62. Bartlett R, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential anti-rheumatic activity - I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol. 1985;7:7-18.
63. Glant TT, Mikecz K, Bartlett RR, et al. Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide. Immunopharmacology. 1992;23:105-16.
64. Bartlett RB, Anagnostopulos H, Zielisnki T, Mattar T, Schleyerbach R. Effects of leflunomide on immune system responses and models of inflammation. Springer Semin Immunopathol. 1993;14:381-94.
65. Schorlemmer HU, Brendel S, Bartlett RR. Malononitrilamides prevent the development of murine systemic lupus erythematosus-like diseases in BDFI mice and MRL/Ipr autoimmune mice. Transplant Proc. 1996;28(6):3040-42.
66. Schorlemmer HU, Kurrle R, Bartlett RR. Malononitri- lamides inhibit the development of various murine graft-vs-host disease. Transplant Proc. 1996;28(6):3043-7.
67. Kuchle CCA, Thoenes GH, Langer KH, Schorlemmer HU, Bartlett RR, Schleyerbach R. Prevention of kidney and skin graft rejection in rats by leflunomide, a new immunomodulating agent. Transplant Proc. 1991:23(1):1083-6.
68. Schorlemmer HU, Seiler FR, Bartlett RR. Prolongation of allogeneic transplanted skin grafts and induction of tolerance by leflunomide, a new immunosuppressive isoxazol derivative. Transplant Proc. 1993;25(1):763-7.
69. McChesney LP, Xao F, Sankary HN, Foster PF, Sharma S, Haklin M, et al. An evaluation of leflunomide in the canine renal transplantation model. Transplantation. 1994;57(12):1717-22.
70. Lirtzmam RA, Gregory CR, Levtski RE, Griffey SM, Yeh L-S, Patz JD, et al. Combined immunosuppression with leflunomide and cyclosporine prevents MLR mismatched renal allograft rejection in mongrel dogs. Transplant Proc. 1996;28(2):945-7.
71. D'Silva M, Candinas D, Achilleos O, Lee S, Antoniou E, DeRoover A, et al. The immunomodulatory effect of leflunomide in rat cardiac allotransplantation. Transplantation. 1995;60(5):430-7.
72. Candinas D, Achilleos O, Lee SJ, Dalgic A, Mayer AD, Buckels JAC, et al. Efficacy of leflunomide in combination with current immunosuppression agents in rats/cardiac allotransplantation. Transplant Proc. 1994;26(6):3251-2.
73. D'Silva M, Antoniou E, DeRoover A, Nishimura Y, Howie A, McMaster P. Immunosuppressive effect of Brequinar on rat cardiac allograft survival in combination with leflunomide or FK506. Transplant Proc. 1996;28(2): 950-1.
74. D'Silva M, Antoniou E, DeRoover A, Nishimura Y, Howie A, McMaster P. Immunosuppressive effect of RS-61443 on rat cardiac allograft survival in combination with leflunomide or FK 506. Transplant Proc. 1996;28(2):930-1.
75. Yuh DD, Gandy KL, Morris RE, Hoyt G, Gutierrez J, Reitz B, et al. Leflunomide prolongs pulmonary allograft and xenograft survival. J Heart Lung Transplant. 1995; 14(6):1136-44.
76. Foster PF, Xiao F, Kociss K, Chong AS-F, Sankary HN, McChesney L, et al. Leflunomide immunosuppression in rat small intestinal transplantation. Transplant Proc. 1994;26(3):1599-1600.
77. He G, McAlister VC, Lee TDG, Bitter-Suerman H, Theal M, Wright J, et al. Oral leflunomide prevents small bowel allograft rejection in the rat. Transplant Proc. 1994; 26(3):1613.
78. D'Silva M, DeRoover A, Nishimura Y, Antoniou E, Candinas D, Hubscher SG, et al. Spectrum of susceptibility to rejection of heart and multivisceral small bowel allografts using leflunomide immunosuppression. Transplant Proc. 1996;28(2):948-949.
79. Yeh L-S, Gregory CR, Griffey SM, Lecourteur RA, Morris RE. Effects of leflunomide and cyclosporine on myocutaneous allograft survival in the rat. Transplantation. 1996;62(6):861-3.
80. Yeh L-S, Gregory CR, Griffey SM, Lecouter RA, Morris RE. Combination of leflunomide and cyclosporine prevents rejection of functional whole limb allografts in the rat. 2nd International Conference on New Trends in Clinical and Experimental Immunosuppression, Geneva, Switzerland, 1996.
81. MacDonald AS, Sabr K, MacAuley MA, McAlister VC, Bitter-Suerman H, Lee T. Effects of leflunomide and cyclosporine on aortic allograft chronic rejection in the rat. Transplant Proc. 1994;26(6):3244-5.
82. Swan SK, Crary GS, O'Donnell MP, Keane WF, Kasiske BL. Immunosuppressive effects of leflunomide in experimental chronic vascular rejection. Transplantation. 1996; 60(8):887-90.
83. Morris RE, Huang X, Gregory CR, Billingham ME, Rowan R, Shorthouse R, et al. Studies in experimental models of chronic rejection: use of rapamycin (Sirolimus) and isozaxol derivatives (Leflunomide and its analogue) for the suppression of graft vascular disease and obliterative bronchiolitis. Transplant Proc. 1995;27(3):2068-9.
84. Xiao F Chong AS-F, Shen J, Yang J, Short J, Foster P, et al. Pharmacoligical induced regression of chronic transplant rejection. Transplantation. 1995;60(10):1065-72.
85. Ulrichs K, Kaitschick J, Bartlett R, Müller-Ruchholtz. Suppression of natural xenophile antibodies with the novel immunomodulating drug loflunomide. Transplant Proc. 1992;24(2):718-9.
86. Xiao F, Chong AS, Forster P, Sankary H, McChesney L, Koukoulis G, et al. Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation. 1994;58(7):828-34.
87. Lin Y, Sobis H, Vandeputte M, Waer M. Long-term xenograft survival and suppression of xenoantibody formation in the hamster-to-rat heart transplant model using a combination therapy of leflunomide and cyclosporine. Transplant Proc. 1994;26(6):3202.
88. Lin Y, Sobis H, Vandeputte M, Woer M. Induction therapy of leflunomide and cyclosporine allows for long-term xenograft survival under cyclosporine alone. Transplant Proc. 1994;26(5):3052.
89. Lin Y, Waer M. In vivo mechanism of action of leflunomide: Selective inhibition of the capacity of lymphocytes to make T-independent xenoantibodies. Transplant. Proc. 1996;28 (6):3085-6.
90. Lin Y, Vandeputte M, Waer M. Difference in tolerization of T-independent and T-dependent xenoantibody formation after cardiac xenotransplantation in rats. Transplant Proc. 1996;28(2):741.
91. Lin Y, Vandeputte M, Waer M. Mechanisms involved in long-term hamster-to-rat cardiac xenograft survival. Transplant Proc. 1996;28(2):683.
92. Salomon S, Steinbrüchel DA, Nielsen B, Lillevang S, Kemp E. Effect of leflunomide, cyclosporine, and splecnectomy in two different organ systems of concordant xenotransplantation in rats. Transplant. Proc. 1996;28(2):698-9.
93. Lakey JRT, Yatscoff RW, Koshal A, Rajotte RV. Prolongation of concordant islet xenografts with leflunomide. Transplant Proc. 1996;28(2):816.
94. Wright JR, Kearns H, McDouglas AS. Leflunomide and cyclosporin-A prolong fish-to-mouse islet xenograft survival in RALB/C mice. Transplant Proc. 1994;26(3):1310.
95. Lin Y, Vandepute M, Waer M. Effect of leflunomide and cyclosporine on the occurrence of chronic xenograft lesions. Kidney Int. 1995;48(suppl 52):S23-8.
96. Chong AS-F, Shen J, Xiao F, Blinder L, Wei L, Sankary H, et al. Delayed xenograft rejection in the concordant hamster heart into Lewis rat model. Transplantation. 1996; 62(1):90-6.
97. Lin Y, Segers C, Waer M. Efficacy of the Malononitrilamide X 920715 as compared with leflunomide in cardiac allo-and xenotransplantation in rats. Transplant Proc. 1996; 28(8):3036.
98. Lucien J, Dias VC, Legatt DF, Yatscoff R. The blood distribution and single dose phamacokinetic of leflunomide. Ther Drug Monit. 1995;17:454-9.
99. Silva HT, Shorthouse R, Morris RE. Single- and multiple-dose pharmacokinetics and pharmacodynamics of leflunomide's active metabolite A77 1726 in normal Lewis rats. Transplant Proc. 1996;28(6):3092-4.
100. Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum. 1995;38(11):1595-1603.
101. Scott DL, Strand V. Leflunomide: A new immunosuppresive drug. In: V Strand, Scott DL, Simon LS, eds. Novel Therapeutic Agents for the Treatment of Autoimmune Diseases. New York, Marcel Dekker, Inc., 1997;287-93.