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Chemical Compound Review

Restasis     (3S,6S,9S,12R,15S,18S,21S,24S, 30S,33S)-30...

Synonyms: Sandimmun, Neoral, Sandimmune, Ciclosporin, Cyclosporin, ...
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Disease relevance of cyclosporine

  • Hepatitis B virus (HBV) DNA-transfected hepatoma cells were incubated with the immunosuppressive agents prednisolone, azathioprine, and cyclosporin A (CsA) and the antiviral agents ganciclovir and foscarnet to investigate the effects of these compounds on HBV replication [1].
  • Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA) [2].
  • Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver [2].
  • In contrast, IFN-alpha/beta production by Newcastle disease virus-infected spleen cells, bone marrow cells, or L cells was not inhibited by the addition of CsA (1 microgram/ml) [3].
  • Decreases in transplant function may be attributable to a variety of conditions, including prerenal and postrenal failure, cyclosporin A (CsA) toxicity, polyoma nephritis, recurrent glomerulonephritis, and rejection [4].

High impact information on cyclosporine

  • A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex [5].
  • CD16 (Fc gamma RIIIA)-induced expression of cytokine mRNA in NK cells occurs via a CsA-sensitive and Ca(2+)-dependent mechanism [6].
  • This occurs with fast kinetics after stimulation, via a CsA-sensitive and Ca(2+)-dependent mechanism that does not require de novo protein synthesis [6].
  • TNF-alpha gene transcription is also highly inducible, CsA-sensitive, and protein synthesis-independent in B cells stimulated through their surface immunoglobulin receptors [7].
  • The ability of analogues of CsA and FK506 to block calcineurin phosphatase activity correlates completely with their ability to inhibit induction of TNF-alpha mRNA, induction of a TNF-alpha promoter reporter plasmid in transiently transfected T cells, and induction of the kappa 3 binding factor in an electrophoretic mobility shift assay [7].

Chemical compound and disease context of cyclosporine


Biological context of cyclosporine


Anatomical context of cyclosporine

  • SAC-, PMA plus SAC-, and PMA plus anti-mu-stimulated, but not PMA-stimulated, increases in TNF mRNA accumulations in tonsillar B cells were inhibited by CsA [15].
  • Furthermore, it is not inhibited by cyclosporin A (CsA), in contrast to NK cell cytotoxicity against the K562 target cell line which is augmented by interferon, inhibited by CsA, and not affected by MVF [16].
  • The effect of CsA on IFN production by alloantigen-stimulated bone marrow and spleen cells was investigated [3].
  • On the contrary, RAP diminished the autonomous proliferation of hybridoma cells, whereas FK-506 and CsA had little effect [17].
  • Ceramide replaced TNF in killing L929 fibroblasts, an effect also prevented by CyA plus ArA [18].

Associations of cyclosporine with other chemical compounds

  • To test this, cyclosporin-A (CyA), a T-lymphocyte function inhibitor known to suppress CSA production in PWM-SCM, was added to marrow cultures in the presence of 2 mM Li [19].
  • The MPT was demonstrated independently of its effect on viability as the CyA-sensitive loss of rhodamine 123 fluorescence from cells preloaded with the dye [18].
  • From these results, the synergistic effect of FTY720 combined with CsA on prolongation of allograft survival is presumably based on the respective inhibitions of T cell infiltration and cytokine production in grafts [20].
  • In such a system, as well as in normal T cells stimulated with high ionomycin concentrations, FK-506 and CsA enhanced proliferation, indicating that they both abrogate negative signals associated with T cell activation [17].
  • Cyclosporin A (CsA) completely blocked the activation-induced death of T cell hybridomas, but actually enhanced the killing caused by Dex [21].

Gene context of cyclosporine

  • Double mutant calcineurin A subunits (Y377F, W388C CMP1 and Y419F, W430C CMP2) confer resistance to CsA, to FK506 and to CsA plus FK506 [12].
  • The immunosuppressant and cytotoxic effects of CsA are thought to result from formation of a toxic complex between cyclophilin and CsA rather than from inhibition of cyclophilin function [22].
  • Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity [23].
  • Similarly, murine mdr3 expression confers resistance to the immunosuppressants cyclosporin A (CsA) and FK506 in a CsA-FK506-sensitive vph6 mutant yeast strain [24].
  • SDZ PSC 833, a non-immunosuppressive analogue of cyclosporin A (CsA), is another potent MDR-reversing drug [25].

Analytical, diagnostic and therapeutic context of cyclosporine

  • CONCLUSIONS: Alloimmune injury induces the expression of PDGF ligands, especially of PDGF-AA, in the graft vasculature and sufficient immunosuppression with CsA suppresses the expression of PDGF and inhibits the development of CAV [26].
  • Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days [2].
  • CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A [27].
  • When PSC concentrations obtained by the TDx CsA assay were divided by 0.17, we found agreement between the TDx CsA assay and the HPLC PSC assay for samples from nine patients [28].
  • Using CsA affinity chromatography, only one cyclophilin with a molecular mass of about 17.8 kDa was separated [29].


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  2. CD4+ T cells mediate murine syngeneic graft-versus-host disease-associated colitis. Bryson, J.S., Zhang, L., Goes, S.W., Jennings, C.D., Caywood, B.E., Carlson, S.L., Kaplan, A.M. J. Immunol. (2004) [Pubmed]
  3. T cell regulation of interferon-alpha/beta (IFN-alpha/beta) production by alloantigen-stimulated bone marrow cells. Reyes, V.E., Klimpel, K.D., Klimpel, G.R. J. Immunol. (1985) [Pubmed]
  4. Steroid-resistant kidney transplant rejection: diagnosis and treatment. Bock, H.A. J. Am. Soc. Nephrol. (2001) [Pubmed]
  5. Structure-based design of a cyclophilin-calcineurin bridging ligand. Alberg, D.G., Schreiber, S.L. Science (1993) [Pubmed]
  6. Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding. Aramburu, J., Azzoni, L., Rao, A., Perussia, B. J. Exp. Med. (1995) [Pubmed]
  7. Calcineurin mediates human tumor necrosis factor alpha gene induction in stimulated T and B cells. Goldfeld, A.E., Tsai, E., Kincaid, R., Belshaw, P.J., Schrieber, S.L., Strominger, J.L., Rao, A. J. Exp. Med. (1994) [Pubmed]
  8. Treatment of severe steroid-dependent nephrotic syndrome (SDNS) in children with tacrolimus. Sinha, M.D., MacLeod, R., Rigby, E., Clark, A.G. Nephrol. Dial. Transplant. (2006) [Pubmed]
  9. The value of C2 monitoring in stable renal allograft recipients on maintenance immunosuppression. Einecke, G., Mai, I., Fritsche, L., Slowinski, T., Waiser, J., Neumayer, H.H., Budde, K. Nephrol. Dial. Transplant. (2004) [Pubmed]
  10. Mast cell subpopulations in gingival overgrowth induced by immunosuppressive and nifedipine medication. Nurmenniemi, P.K., Pernu, H.E., Knuuttila, M.L. J. Periodontol. (2004) [Pubmed]
  11. Allogeneic peripheral blood stem cell transplantation in 23 adult patients with hematologic malignancies: a single-center experience. Takenaka, K., Shinagawa, K., Sunami, K., Fujii, N., Hiramatsu, Y., Maeda, Y., Nawa, Y., Katayama, Y., Teshima, T., Ishimaru, F., Kiura, K., Ikeda, K., Harada, M. Int. J. Hematol. (2000) [Pubmed]
  12. Targets of immunophilin-immunosuppressant complexes are distinct highly conserved regions of calcineurin A. Cardenas, M.E., Muir, R.S., Breuder, T., Heitman, J. EMBO J. (1995) [Pubmed]
  13. Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction. Shim, J.H., Lee, H.K., Chang, E.J., Chae, W.J., Han, J.H., Han, D.J., Morio, T., Yang, J.J., Bothwell, A., Lee, S.K. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  14. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Woronicz, J.D., Lina, A., Calnan, B.J., Szychowski, S., Cheng, L., Winoto, A. Mol. Cell. Biol. (1995) [Pubmed]
  15. Production of tumor necrosis factor/cachectin by human B cell lines and tonsillar B cells. Sung, S.S., Jung, L.K., Walters, J.A., Chen, W., Wang, C.Y., Fu, S.M. J. Exp. Med. (1988) [Pubmed]
  16. Membrane markers, target cell specificity, and sensitivity to biological response modifiers distinguish human natural cytotoxic from human natural killer cells. Rola-Pleszczynski, M., Lieu, H., Sullivan, A.K., Girard, M. J. Clin. Invest. (1985) [Pubmed]
  17. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. Dumont, F.J., Staruch, M.J., Koprak, S.L., Melino, M.R., Sigal, N.H. J. Immunol. (1990) [Pubmed]
  18. The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition. Pastorino, J.G., Simbula, G., Yamamoto, K., Glascott, P.A., Rothman, R.J., Farber, J.L. J. Biol. Chem. (1996) [Pubmed]
  19. Lithium enhancement of megakaryocytopoiesis in culture: mediation via accessory marrow cells. Chatelain, C., Burstein, S.A., Harker, L.A. Blood (1983) [Pubmed]
  20. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. Yanagawa, Y., Sugahara, K., Kataoka, H., Kawaguchi, T., Masubuchi, Y., Chiba, K. J. Immunol. (1998) [Pubmed]
  21. Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic. Zacharchuk, C.M., Merćep, M., Chakraborti, P.K., Simons, S.S., Ashwell, J.D. J. Immunol. (1990) [Pubmed]
  22. A yeast cyclophilin gene essential for lactate metabolism at high temperature. Davis, E.S., Becker, A., Heitman, J., Hall, M.N., Brennan, M.B. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  23. Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells. Boussiotis, V.A., Nadler, L.M., Strominger, J.L., Goldfeld, A.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  24. Immunosuppressant target protein FKBP12 is required for P-glycoprotein function in yeast. Hemenway, C.S., Heitman, J. J. Biol. Chem. (1996) [Pubmed]
  25. New multidrug-resistance-reversing drugs, MS-209 and SDZ PSC 833. Naito, M., Tsuruo, T. Cancer Chemother. Pharmacol. (1997) [Pubmed]
  26. Expression and localization of platelet-derived growth factor ligand and receptor protein during acute and chronic rejection of rat cardiac allografts. Lemström, K.B., Koskinen, P.K. Circulation (1997) [Pubmed]
  27. Cyclophilin D as a drug target. Waldmeier, P.C., Zimmermann, K., Qian, T., Tintelnot-Blomley, M., Lemasters, J.J. Current medicinal chemistry. (2003) [Pubmed]
  28. HPLC method for monitoring SDZ PSC 833 in whole blood. Scott, M.G., Hock, K.G., Crimmins, D.L., Fracasso, P.M. Clin. Chem. (1997) [Pubmed]
  29. Oxygen stress increases prolyl cis/trans isomerase activity and expression of cyclophilin 18 in rabbit blastocysts. Santos, A.N., Körber, S., Küllertz, G., Fischer, G., Fischer, B. Biol. Reprod. (2000) [Pubmed]
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