74
Views
47
CrossRef citations to date
0
Altmetric
Drug Evaluation

Leflunomide and malononitriloamides

, &
Pages 51-64 | Published online: 23 Feb 2005

Bibliography

  • BARTLETT RR, CAMPION G, MUSIKIC P, SCHLEYERBACH R: Leflunomide: a novel immunomodulating drug. In: Non-steroidal Anti-inflammatory Drugs: Mechanisms and Clinical Uses (Second Edition). Furst AJLDE (Ed.), Marcel Dekker, Inc., New York, Basel, Hong Kong (1994):349–366.
  • AXTON CA, BILLINGHAM MEJ, BISHOP PM et al.: Novel immunosuppressive butenamides. J. Chem. Soc. Perkin Trans. (1992) 1:2203–2213.
  • WILLIAMSON RA, YEA CM, ROBINSON PA et al: Dihydro-orotate dehydrogenase, a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J. Biol. Chem. (1995) 270:22467–22472.
  • 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) 220:266–273.
  • ULLRICH A, SCHLESSINGER J: Signal transduction byreceptors with tyrosine kinase activity. Cell (1990) 61:203–212.
  • XU X, WILLIAMS JW, BREMER EG, FINNEGAN A, CHONG AS-F: Inhibition of protein tyrosine kinase phosphory-lation in T-cells by a novel immunosuppressive agent, leflunomide. J. Biol. Chem. (1995) 270:12398–12403.
  • NIKCEVICH DA, FINNEGAN A, CHONG AS-F, WILLIAMS JW, BREMER EG: Inhibition of interleukin 2 (IL-2)-stimu-lated tyrosine kinase activity by leflunomide. Agents Actions (1994) 41:C279–C282.
  • XU X, WILLIAMS JW, GONG H, FINNEGAN A, CHONG AS-F: Two activities of the immunosuppressive metabolite leflunomide, A77 1726: inhibition of pyrimidine nu-cleotide synthesis and protein tyrosine phosphoryla-lion. Biochem. Pharmacol. (1996) 52:527–534.
  • JONE ME: Pyrimidine nucleotides biosynthesis in ani-mals: genes, enzymes, and regulation of UMP biosyn-thesis. Ann. Rev. Biochem. (1980) 49:253–256.
  • DEVLIN TM: Textbook of Biochemistry with Clinical Correla-tions (Third Edition). John Wiley & Sons, Inc., Philadelphia (1992).
  • MARIJNEN YMT, KORTE DD, HAVERKORT WA eta].: Stud-ies onthe incorporation of precursors into purine and pyrimidine nucleotides via' de novo' and 'salvage' path-ways in normal lymphocytes and lymphoblastic cell-line cells. Biochim. Biophys. Acta (1989) 1012:148–155.
  • FAIRBANKS LD, BOFILL M, RUCKEMAN K, SIMMONDS HA: Importance of ribonucleotide availability to proliferat-ing T-lymphocytes from healthy humans. j Biol. Chem. (1995) 270:29682–29689.
  • SIMMONDS HA: Diagnosis and treatment of inborn errors of purine and pyrimidine metabolism: an over-view. Adv. Exp. Med. Biol. (1994) 370:1–6.
  • PETERS GJ, VEERKAMP JH: Plaine and pyrimidine meta-bolism in the peripheral blood lymphocytes. Int J. Biochem. (1983) 15:115–123.
  • BARANKIEWICZ J, COHEN A: Purine nucleotide metabo-lism in phytohemagglutinin-induced human T-lym-phocytes. Arch. Biochem. Biophys. (1987) 258:167–175.
  • WEBER G: Biochemical strategy of cancer cells and design of chemotherapy: GHA Clowes memorial lec-ture. Cancer Res. (1983) 43:3466–3492.
  • 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 ribonu-cleotide metabolism. Mol. Pharmacol (1992) 41:671–676.
  • PETERS G, SCHWARTSMANN G, NADAL J et al: In vivo inhibition of the pyrimidine de novo enzyme dihydro-orotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Res. (1990) 50:4644–4649.
  • ALLISON AC, EUGUI EM: Inhibitors of de novo purine and pyrimidine synthesis as immunosuppressive drugs. Transplant Proc. (1993) 25:8–18.
  • ANGERMeLLER S, LOFFLER M: Localization of dihydro-orotate oxidase in myocardium and kidney cortex of the rat. Histochemistry (1995) 103:287–292.
  • GREENE S, WATANABE K, BRAATZ-TRULSON J, LOU L: Inhibition of dihydro-orotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem. Phar-macol (1995) 50:861–867.
  • DAVIS JP, CAIN GA, PITTS WJ, MAGOLDA RL, COPELANDRA: The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydro-orotate dehy-drogenase. Biochemistry (1996) 35:1270–1273.
  • CHERWINSKI HM, MCCARLEY D, SCHATZMAN R, DEVENSB, RANSOM JT: The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism. J. Pharmacol. Exp. Ther. (1995) 272:460–468.
  • 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, ongo-ing rejection, and antidonor antibody synthesis in mouse, rat, and cynomolgus monkey transplant recipi-ents as well as arterial intimal thickening after balloon catheter injury. Transplant. Proc. (1995) 27:445–447.
  • MATTAR T, KOCHHAR K, BARTLETT R, BREMER EG, FIN-NEGAN A: Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflummide. FEBS Lett. (1993) 334:161–164.
  • CAO WW, KAO PN, CHAO AC et al: Mechanism of theanti-proliferative action of Leflunomide. A771726, the active metabolite of leflunomide, does not block T-cell receptor-mediated signal transduction but its antipro-liferative effects are antagonized by pyrimidine nucleosides. J. Heart Lung Transplant. (1995) 14:1016–1030.
  • NAIR RV, CAO W, MORRIS RE: Inhibition of smooth muscle cell proliferation in vitro by leflunomide, a new immunosuppressant, is antagonized by uridine. /mm u-no/. Lett. (1995) 47:171–174.
  • SIEMASKO KF, CHONG ASF, WILLIAMS JW, BREMMER EG, FINNEGAN A: Regulation of B-cell function by the im-munosuppressive agent leflunomide. Transplantation (1996) 61:635–642.
  • CHONG AS-F, FINNEGAN A, JIANG X et al: Leflunomide, a novel immunosuppressive agent: the mechanism of inhibition of T-cell proliferation. Transplantation (1993) 55:1361–1366.
  • ZIELINSKI T, MULLER H-J, BARTLETT RR: Effects of le-flunomide (HWA 486) on expression of lymphocyte activation markers. Agents Actions (1993) 38:80–82.
  • LANG R, WAGNER H, HEEG K: Differential effects of the immunosuppressive agents cyclosporine and le-flunomide in vivo. Transplantation (1995) 59:382–389.
  • KHANA A, LI B, STENZEL KH, SUTHANTHIRAN M: Regula-tion of new DNA synthesis in mammalian cells by cyclosp or ine . Demonstration of a transforming growth factor beta-dependent mechanism of inhibition of cell growth. Transplantation (1994) 57:577–582.
  • CAO WW, KAO PN, AOKI Y eta].: A novel mechanism of action of the immunomodulatory drug, leflunomide: augmentation of the immunosuppressive cytokine, TGF-131, and suppression of the immunostimulatory cytokine, 11–2. Transplant. Proc. (1996). In press.
  • BARTLETT R: Immunopharmacological profile of HWA 486, a novel is oxazol derivative - II. In vivo immuno-modulating effects differ from those of cyclophos-phamide, prednisone, or cyclosporin A. Int. J. Immunopharmacol (1986) 8:199–204.
  • CHERWINSKI HM, VVEBSTER DJ, RANSOM JT: The immu-nosuppressive/anti-inflammatory molecule le-flunomide causes apoptosis in mitogen stimulated human T-cells. 9th International Congress of Immunology San Francisco, CA (1995). Abstract 5113.
  • LINKE SP, CLARKIN KC, LEONARDO AD, TSOU A, WAHL GM: A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Gene Dev. (1996) 10:934–947.
  • PALLADINO MA, MORRIS RE, STARNES HF, LEVINSON AD: The transforming growth factor-betas. A new family of immunoregulatory molecules. Ann. NY Acad. ScL (1990) 593:181–187.
  • SHERR CJ: G1 phase progression: cycling on cue. Cell(1994) 79:551–555.
  • ALLISON AC, KOWASLSKI WJ, MULLER CJ, WATERS RV, EUGUI EM: Mycophenolic acid and brequinar, inhibi-tors of purine and pyrimidine synthesis, block the glycosylation of adhesion molecules. Transplant Proc. (1993) 25:67–70.
  • DIMITRIJEVIC M, BARTLETT RR Leflunomide, a novel immunomodulating drug inhibits homotypic adhesion of mononuclear cells in rheumatoid arthritis. 2nd Inter- national Conference on New trends in Clinical and Experi-mental Immunosuppression. Geneva, Switzerland (1996):165.
  • BARTLETT RR, MATTAR T, WEITHMANN U et al: Le-flunomide (HWA 486): a novel immumrestoring drug. Therapeutic Approaches to Inflammatory Diseases (1988):215–228.
  • WEITHMANN KU, JESKE S, SCHLOTTE V: Effect of le-flunomide on constitutive and inducible pathways of cellular eicosanoid generation. Agents Actions (1994) 41:164–170.
  • SILVA HT, CAO W, SHORTHOUSE R, MORRIS RE: Mecha-nism of action of leflunomide: in vivo administration of uridine reverses its inhibition of lymphocyte prolif-eration. Transplant. Proc. (1996) 28:3082–3084.
  • SILVA HT, CAO W, SHORTHOUSE R, LOFLLER M, MORRIS RE: In vitro and in vivo effects of leflunomide (LFM), brequinar (BQR) and cyclosporine (CsA) on pyrimidine biosynthesis. Transplant Proc. In press.
  • GLANT TT, MIKECZ K, BRENNAN F, NEGROIU G, BAR-TLETT R: Suppression of autoimmune responses and inflammatory events by leflunomide in an animal model for rheumatoid arthritis. Agents Actions (1994) 41:C267–C270.
  • BARTLETT RB, DIMITRIJEVIC M, MATTAR T et al: Le-flunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. AgentsActions (1991) 32:10–21.
  • POPOVIC S, BARTLETT R: Disease modifying activity of HWA 486 on the development of SLE in MRL/l-mice. Agents Actions (1986) 19:313–314.
  • POPOVIC S, BARTLETT R: The use of murine chroni c graft vs. host (CGVH) disease, a model for systemic lupus erythematosus (SLE), for drug discovery. Agents Actions (1987) 21:284–286.
  • VIDIC-DANKOVIC B, KOSEC D, DAMJANOVIC M et al: Leflunomide prevents the development of experimen-tally induced myasthenia gravis. Int. J. Immunopharma-col. (1995) 17:273–281.
  • THOENES G, SITTER T, LANGER K, BARTLETT R, SCHLEY-ER BACH R: Leflunomide (HWA 486) inhibits experimen-tal autoimmune tubulointerstitial nephritis in rats. Int Immunopharmacol. (1989) 11:921–929.
  • OGAWA T, INAZU M, GOTOH K, INOUE T, HAYASHI S: Therapeutic effects of leflunomide, a new antirheu-matic drug, on glomerulonephritis induced by an-tibasement membrane antibody in rats. Clin. Immunol Immunopharmacol (1991) 61:103–118.
  • ROBERTSON SM, LANG LS: Leflunomide: inhibition of S-antigen induced autoimmune uveitis in Lewis rats. Agents Actions (1994) 42:167–172.
  • WILLIANS JW, XAO F, FORSTER P et al: Leflunomide in experimental transplantation. Transplantation (1994) 57:1223–1231.
  • 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) 27:305–306.
  • LUCIEN J, MARATH A, RAYAT G et al.: Efficacy of leflunomide to reduce xenoantibody titers in vivo: an evaluation of prolongation of discordant xenograft survival. Transplant Proc. (1996) 28:704–707.
  • CHEUNG A, BILLINGHAM M, ZHENG B et al: Leflunomide abrogates hyperacute heart allograft rejection in pre-sensitized rats. Transplant. Proc. (1996) In press.
  • BARTLETT R, SCHLEYERBACH R: Immunopharmacologi-cal profile of a novel is oxazol derivative, HWA 486, with potential anti-rheumatic activity - L Disease modifying action on adjuvant arthritis of the rat. Int. J. Immuno-pharmacol (1985) 7:7–18.
  • GLANT IT, MIKECZ K, BARTLETT RR et al: Immunomodu-lation of proteoglycan-induced progressive polyarthri-tis by leflunomide. Immunopharmacology (1992) 23:105–116.
  • BARTLETT RB, ANAGNOSTOPULOS H, ZIELISNKI T, MAT-TAR T, SCHLEYERBACH R: Effects of leflunomide on immune system responses and models of inflamma-tion. Springer Semin. Immunopathol. (1993) 14:381–394.
  • KURTZ ES, BAILEY SC, ARSHAD F, LEE A, PRZEKOP PA:Leflunomide: an active anti-inflammatory and antip ro-liferative agent in models of dermatologic disease. In-flamm. Res. (1995) 44:S187–S188.
  • MCCHESNEY LP, XAO F, SANKARY HN eta].: An evaluationof leflunomide in the canine renal transplantation model. Transplantation (1994) 57:1717–1722.
  • LIRTZMAN RA, GREGORY CR, LEVTSKI RE et al: Combinedimmunosuppression with leflunomide and cyclospor-ine prevents MLR mismatched renal allograft rejection in mongrel dogs. Transplant Proc. (1996) 28:945–947.
  • XIAO F, CHONG AS, FORSTER P et al: Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation (1994) 58:828–834.
  • SCHORLEMMER HU, SEILER FR, BARTLETT RR: Prolonga-tion of allogeneic transplanted skin grafts and induc-tion of tolerance by leflunomide, a new immunosuppressive frixazol derivative. Transplant Proc. (1993) 25:763–767.
  • D'SILVA M, CANDINAS D, ACHILLEOS O et al: The immu-nomodulatory effect of leflunomide in rat cardiac alto-transp lantat ion. Transplantation (1995) 60:430–437.
  • MORRIS RE, HUANG X, GREGORY CR et al: Studies in experimental models of chronic rejection: use of ra-pamycin (Sirolimus) and isozaxol derivatives (le-flunomide and its analogue) for the suppression of graft vascular disease and obliterative bronchiolitis. Trans-plant. Proc. (1995) 27:2068–2069.
  • SWAN SK, CRARY GS, O'DONNELL MP, KEANE WF, KASISKE BL: Immunosuppressive effects of leflunomide in experimental chronic vascular rejection. Transplan-tation (1996) 60:887–890.
  • UN Y, VANDEPUTE M, WAER M: Effect of leflunomideand cyclosporine on the occurrence of chronic xenograft lesions. Kidney Int (1995) 48:S23–S28.
  • MACDONALD AS, SABR K, MACAULEY MA et al: Effects ofleflunomide and cyclosporine on aortic allograft chronic rejection in the rat. Transplant. Proc. (1994) 26:3244–3245.
  • XIAO F, CHONG AS-F, SHEN J et al: Pharmacologicalinduced regression of chronic transplant rejection. Transplantation (1995) 60:1065–1072.
  • LUCIEN J, DIAS VC, LEGATT DF, YATSCOFF R: The blooddistribution and single dose pharmacokinetics of le-flunomide. Therapeutic Drug Monitoring (1995) 17:454–459.
  • SILVA HT, SHORTHOUSE R, MORRIS RE: Single- and mul-tiple-dose pharmacokinetics and pharmacodynamics of leflunomide's active metabolite A77 1726 in normal Lewis rats. Transplant Proc. (1996) 28:3092–3094.
  • MLADENOVIC V, DOMLJAN Z, ROZMAN B et al: Safety and effectiveness of leflunomide in the treatment of pa-tients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, Phase II study. Arthri-tis Rheumatism (1995) 38:1595–1603.
  • SCOTT DL, STRAND V: Leflunomide: a new immunosup-presive drug. In: Novel Therapeutic Agents for the Treatment of A utoimm une Diseases. Strand V (Ed.), Marcel Dekker, Inc., New York (1997):287–293.
  • OGAWA T, INAZU M, GOTOH K, HAYASHI S: Effects ofleflunomide on glomerulonephritis induced by an-tibasement membrane antibody in rats. Agents Actions (1990) 31:321–328.
  • KUCHLE CCA, THOENES GH, LANGER KH et al.: Preven-tion of kidney and skin graft rejection in rats by leflunomide, a new immunomodulating agent. Trans-plant. Proc. (1991) 23:1083–1086.
  • CANDINAS D, ACHILLEOS O, LEE SJ et al.: Efficacy of leflunomide in combination with current immunosup-pression agents in rat cardiac allotransplantation. Transplant Proc. (1994) 26:3251–3252.
  • MCCHESNEY L, XIAO F, SANKARY H eta].: Evaluation ofleflunomide in the canine renal transplantation model. Transplantation (1994) 57:1717–1722.
  • FOSTER PF, XIAO F, KOCISS K eta].: Leflunomide immu-nosuppression in rat small intestinal transplantation. Transplant Proc. (1994) 26:1599–1600.
  • HE G, MCALISTER VC, LEE TDG et al: Oral leflunomideprevents small bowel allograft rejection in rat. Trans-plant. Proc. (1994) 26:1613.
  • YEH L-S, GREGORY CR, GRIFFEY SM, LECOURTEUR RA,MORRIS RE: Effects of leflunomide and cyclosporine on myocutaneous allograft survival in the rat. Transplanta-tion (1996) 62:861–863.
  • YUH DD, GANDY KL, MORRIS RE et al.: Leflunomide prolongs pulmonary allograft and xenograft survival. J. Heart Lung Transplant. (1995) 14:1136–1144.
  • D'SILVA M, DERO OVER A, NISHIMURA Y eta].: Spectrum of susceptibility to rejection of heart and multivisceral small bowel allografts using leflunomide immunosup-pression. Transplant. Proc. (1996) 28:948–949.
  • LAKEY JRT, YATSCOFF RW, KOSHAL A, RAJOTTE RV: Prolongation of concordant islet xenografts with le-flunomide. Transplant. Proc. (1996) 28:816.
  • SALOMON S, STEINBRÜCHEL DA, NIELSEN B, LILLEVANGS, KEMP E: Effect of leflunomide, cyclosporine, and splenectomy in two different organ system of concor-dant xenotransp lantat ion in rat. Transplant. Proc. (1996) 28:698–699.
  • WRIGHT JR, KEARNS H, MCDOUGLAS AS: Leflunomideand cyclosporin-A prolong fish-to-mouse islet xenograft survival in BALB/C mice. Transplant. Proc. (1994) 26:1310.
  • YEH L-S, GREGORY CR, GRIFFEY SM, LECOUTER RA, MORRIS RE: C ombination of leflunomide and cyclosp or-ine prevents rejection of ftmctional whole limb allo-grafts in the rat. 2nd International Conference on New Trends in Clinical and Experimental Immunosuppression. Geneva, Switzerland (1996):121.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.