Cyclosporine inhibition

Through regulation of gene transcription, cyclosporine inhibits interleukin-1 and interleukin-2 receptor production and secondarily inhibits macrophage-T-cell interaction and T-cell responsiveness (see Chapter 55). T-cell-dependent -cell function is also affected. 

Fig. 4.1 Mechanism of action of cyclosporine. Cyclosporine readily diffuses into the cytoplasm of the target cells where it binds to cyclophilins. The cyclosporine-cyclophilin complex stably associates with calcineurin and inhibits calcineurin activity. Calcineurin is a Ca2+-dependent enzyme— serine/threonine phosphatase— which after activation by Ca2+, dephosphorylates a cytosolic component of NFAT (NFATc, cytosolic factor of activated T cells). After dephosphorylation, NFATc migrates from the cytoplasm to the nucleus where it associates with NFATn and induces transcription of several cytokine genes including IL-2. Cyclosporine inhibits calcineurin activity after associating with cyclophilins, resulting in the inhibition of IL-2 production and other cytokines (see Color Insert)...

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

Strong B, Farley W, Stern ME, Pflugfeelder SC. Topical cyclosporine inhibits conjimctival epithelial apoptosis in experimental murine keratoconjimctivitis sicca. Cornea 2005 24 80-85. 

Nell A, Matejka M, Solar P, Ulm C, Sinzinger H. Evidence that cyclosporine inhibits periodontal prostaglandin 12 synthesis. J Periodontal Res 1996 31(2) 131. ... 

Gaston RS,SchlessingerSD, Sanders PW, Barker CV, Curtis JJ,WarnockDG. Cyclosporine inhibits the renal response to L-argInIne in human kidney transplant recipients. J Am Soc Nephrol 995 5 1426-1433. 

Cyclosporine inhibits the metabolism of Ever, requiring Ever dose reduction when co-administered with CyA simultaneous administration of CyA and Ever is expected to be the usual approach to immunosuppression. Ever does not affect CyA metabolism. The primary side effect of concern with Ever therapy is hyperlipidemia. ... 

Tacrolimus is a macrohde immunosuppressive agent indicated for the prevention of organ transplant rejection and useful as an alternative treatment in severe recalcitrant psoriasis. Tacrolimus, like cyclosporine, inhibits T-ceU activation. ... 

Smdies in the 1970s showed that cyclosporin inhibits humoral immunoreactions, and that it had a selective effect on T-cell dependent immunoreactions and that its effect was reversible. Cyclosporin is considered to interfere with the process for primary T-cell activation. In this way the formation of T-effector cells, cytotoxic T-lymphocytes or killer lymphocytes, which have the dominant function in cell mediated immune reactions like rejecting an allograft in transplantation surgery and delayed hypersensitivity reaction, is prevented. 

Th lymphocytes recognize foreign antigens presented by APC cells and, once activated, secrete cytokines that drive cell-mediated immunity (see Figure 56-2). The answer is (E). Cyclosporine inhibits calcineutin, a serine phosphatase that is needed for activation of T cell-specific transcription factors. Gene transcription of IL-2, IL-3, and interferon-y is inhibited. The answer is (D). 

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. 

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

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. 

Diltiazem Inhibits AV nodal conduction by slowing AV nodal conduction and prolonging AV nodal refractoriness 1.0.25 mg/kg IV load over 2 minutes 2. If necessary, 0.35 mg/kg IV over 2 minutes after first dose Continuous infusion of 5-1 5 mg/hour Oral 120-360 mg/day Inhibits elimination of cyclosporine... 

The calcineurin inhibitors cyclosporine and tacrolimus block T cell activation by inhibiting the production of IL-2. They are associated with significant adverse events, such as nephrotoxicity, cardiovascular disease, posttransplant diabetes, and neurotoxicity. 

Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of medical immunosuppression. The calcineurin inhibitors work by complexingwith cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding protein 12). These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 synthesis and a subsequent reduction in T cell activation.7 11 20 21... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

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