Calcineurin with 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. 

FIGURE 52-2. Center-specific protocols may use RATG, an IL-2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

The metabolism of mycophenolate is altered by coadministration with cyclosporine. Mycophenolic acid (MPA) levels are lower when mycophenolate mofetil is compared with cyclosporine. Lower doses should be considered in recipients receiving tacrolimus or steroids done without a calcineurin inhibitor. 

Ding, B., Price, R. L., Borg, T. K, Weinberg, E. O., Halloran, P. F., and Lorell, B. H. (1999). Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. Circ. Res. 84, 729-734. 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

Jin, L., Harrison, S. C. (2002). Crystal structure of human calcineurin complexed with cyclosporin A and hnman cyclophUin. Proc. Nat. Acad. Sci. USA, 99, 13522-13526. 

The most remarkable advantage for rapamycin is its lack of significant toxicides in the kidney, pancreas, and CNS frequently seen with cyclosporin and tacrolimus and which are believed to occur, in part, due to effects on calcineurin inhibition via the tacrolimus-FKBP or cyclosporin-cyclophilin complex. On the other hand, because rapamycin exerts its effect not only on T cells but also on other cells that are stimulated by the growth factors it inhibits, its effects are not T-cell specific. This means that rapamycin affects several unique biochemical events, giving rise to its own unique pattern of adverse events [69]. Compared to tacrolimus or cyclosporin, rapamycin is associated with a significantly higher incidence of adverse effects such as hypertriglyceridemia, hypercholesterolemia. 

Ivery, M. T. (1999). A proposed molecular model for the interaction of calcineurin with the cyclosporin A-cyclophilin A complex. Bioorg. Med. Chem. 7, 1389-1402. 

Figure 16 (a) The stmcture of calcineurin with suhunit A in cyan. The catalytic site containing a Zn-Fe hinding site is in dark red. Subunit B in orange contains four calcium (green) ions bound to the EF-hand motifs. Both N- and C-terminal domains of calcineurin B interact to the same extended a-helix of calcineurin A. (b) The inhibitor complex cyclosporin A (red) and cyclophilin (violet) interacts with both calcineurin subunits and blocks the catalytic site of calcineurin ... 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

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... 

Although tacrolimus therapy is associated with increasing blood pressure, studies have found that tacrolimus has less dramatic effects on GFR and RBF than cyclosporine. In some clinical trials, tacrolimus caused less severe HTN and required significantly fewer antihypertensive medications at both 24 and 60 months after transplantation than cyclosporine.61-63 Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to minimize blood pressure increases in transplant recipients. Conversion to sirolimus also may be an alternative to the calcineurin inhibitors in patients with difficult-to-treat HTN because sirolimus therapy is less associated with increased blood pressure. Additionally, withdrawal or tapering of steroid therapy may be an effective strategy for lowering blood pressure. 

The immune-suppressing drugs tacrolimus (FK 506) and cyclosporin A target the phosphatase calcineurin that is involved in the dephosphorylation of dynamin. It is reported that the uptake of liposomes was significantly decreased after incubation with FK506 (1 pM, 10 minutes prior incubation with liposomes) (1). 

After transplantation, immunosuppression must be used to prevent host rejection of the graft liver, usually with prednisone and tacrolimus or cyclosporine. Tacrolimus and cyclosporine are calcineurin inhibitors and require drug level monitoring because of a narrow therapeutic range and significant toxicity, including renal failure and neurotoxicity. 

Tacrolimus (previously known as FK506) is a macrolide antibiotic which is obtained from the fungus Streptomyces tsukubaensis. Tacrolimus binds in-tracellularly to the protein FKBP (FK binding protein) which is distinct from the protein that binds cyclosporine. However both drug-protein complexes associate in a similar way with calcineurin and inhibits its serine/threonine phosphatase activity, although the immunosuppressive potency of tacrolimus is approximately 100 fold higher than that of cyclosporine. 

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