Cyclosporin A, inhibition

Shi, Y.F., Sahai, B.M., and Green, D.R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature, 339, 625, 1989... 

The most important activity of cyclosporin A consists clearly in the marked suppression of antibody formation and cell-mediated immune response [4, 5]. In addition, the metabolite exhibits antiphlogistic effects, restricted to chronic inflammation processes, as well as antifungal and antiparasitic activities. Whether these different biological activities are inter-related or represent separate mechanisms is still an open question. Considering immunosuppression, early observations revealed that cyclosporin A acts selectively on lymphocytes, mainly on T cells, affecting rather the inductive phase than the proliferative phase of lymphoid cell populations. Apparently, cyclosporin A inhibits primary T-helper cell activation and blocks the formation of... 

Romanowski EG, Pless P. Topical cyclosporine A inhibits subepitheUal immune infiltrates but also promotes viral shedding in experimental adenovirus models. Cornea 2005 24 86-91. 

The most active metabolite was the novel cyclic undecapeptide, cyclosporin A (Figure 8). As an antibiotic, cyclosporin A exhibited only a very narrow spectrum of modest antifungal activity, but in 1972 its true potential was realised. Jean Borel and colleagues at Sandoz discovered that cyclosporin A also neutralised cytotoxic T-cell activity in vitro and prevented haemagglutination in mice immunised against sheep erythrocytes. Further studies revealed that cyclosporin A inhibits T-cell proliferation by blocking the synthesis of IL-2. ... 

Stahl RA, Adler S, Baker PJ, Johnson RJ, Chen YP, Pritzl P, and Couser WG. Cyclosporin A inhibits prostaglandin E2 formation by rat mesangial cells in culture. Kidney Int 35 1161-1167,1989. 

Storogenko M, Pech-Amsellem MA, Kerdine S, Rousselet E, Pallardy M. Cyclosporin-A inhibits human endothelial cells proliferation through interleukin-6-dependent mechanisms. Life Sci 1997 60 1487-1496. 

Richards NT, Poston L, Hilton PJ. Cyclosporine A inhibits relaxation but does not induce vasoconstriction in human subcutaneous resistance vessels. J Hypertens 1989 7 1-3. 

Ling BN, Eaton DC. Cyclosporin A inhibits apical secretory K-i-channels in rabbit cortical collecting tubule principal cells. Kidney Int 1993 44 974-984. 

IL-3 does not exist in a preformed state, being synthesized after cellular activation. Glucocorticoids and cyclosporin A inhibit IL-3 production by T lymphocytes. ... 

Nussenblatt RB, Rodrigues MM, Wacker WB, Cevario SJ, Salinas-Carmona MC, Gery I. Cyclosporin A. Inhibition of experimental autoimmune uveitis in Lewis rats. J Clin Invest 1981 67 1228-1231. 

A secondary metabolite produced by Tolypocladium inflation. This fungus was initially isolated in a soil sample collected in Norway. Cyclosporin A is a cyclic undecapeptide. Inside cells, cyclosporine A binds its immunophillin receptor known as cyclophillin. Like the FK506-FKBP12 complex, cyclosporin A-cyclophillin binds and inhibits the protein phosphatase calcineurin. 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

Not all transporters, however, show the same preferential directions. Lee and coworkers also have discovered a pump glycoprotein in the conjunctiva with preferential flux directed toward the mucosal side of the tissue. This transporter has been shown to restrict conjunctival absorption of therapeutic agents such as cyclosporin A, verapamil, and dexamethasone. In some circumstances, transient inhibition of such xe-nobiotic transporters might be an effective means of increasing the efficacy of particular classes of therapeutic agents. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Cyclosporin A Transplant rejections Depresses T cells inhibits IL-2 production... 

Kay, J.E. and Benzie, C.R. (1984). Rapid loss of sensitivity of mitogen-induced lymphocyte activation to inhibition by cyclosporin A. Cell Immunol. 87 217-224. 

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