Mycophenolate Cyclosporine

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

ESRD secondary to PCKD and failed previous transplant. One prior renal transplant that occurred in 1995 (received kidney from husband), which failed secondary to chronic allograft nephropathy in 2004 (presumably from multiple rejection episodes within the first few years after transplant). For the previous transplant, the patient was maintained on cyclosporine, mycophenolate, and prednisone. 

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. 

BUN, blood urea nitrogen Cl, calcineurin inhibitor CSA, cyclosporine IL-2RA, interleukin 2 receptor antagonist LFTs, liver function tests MMF, mycophenolate mofetil OKT-3, muronomab-CD3 RATG, rabbit antithymocyte immunoglobulin ... 

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... 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

The combination of cyclosporine with calcipotriol may be more efficacious than either agent used alone.21,37 Cyclosporine and SCAT may also be effective.21,38 However, cyclosporine should not be used concurrently with PIJVA there is a well-documented increased risk of squamous cell cancer and the combination may have a negative effect on lesion clearance.21 The combination of cyclosporine with methotrexate is extremely effective and minimizes toxicity from either agent as discussed. Cyclosporine has also been used successfully with mycophenolate mofetil38 and etanercept.29... 

Mycophenolate mofetil in doses of 1 to 1.5 g twice daily (maximum dose 3 g/day) is effective as adjunctive therapy in patients with resistant psoriasis on cyclosporine.29,38 As monotherapy, there may be some benefit in patients with moderate psoriasis and psoriatic arthritis, but not in severe psoriasis.29... 

A phase II clinical study of FTY720 in de novo renal transplant patients showed superior efficacy of FTY720 compared to mycophenolate mofetil, if combined with cyclosporine A and steroids [57], In a 1 year, multicentre,... 

Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G Perico N. (2005) Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J... 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Renal, cardiac, and hepatic transplant Mycophenolate is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants. Use mycophenolate concomitantly with cyclosporine and corticosteroids. 

Mortaiity The use of daclizumab as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids may be associated with an increase in mortality. 

Echinacea (Echinacea purpurea) Uses immune system stimulant prevention/Rx of colds, flu as supportive th apy for colds chronic infxns of the resp tract lower urinary tract Action Stimulates phagocytosis cytokine production T resp cellular activity topically exerts anesthetic, antimicrobial, anti-inflammatory effects Efficacy Not established may X severity duration of URI Available forms Caps w/ powdered herb equivalent to 300-500 mg, PO, tid pressed juice 6-9 mL, PO, once/d tine 2-4 mL, PO, tid (1 5 dilution) tea 2 tsp (4 g) of powdered herb in 1 cup of boiling water Noles/SE Fever, taste p -version, urticaria, angioedema Contra w/ autoimmune Dz, collagen Dz, progressive systemic Dz (TB, MS, collagen-vascular disorders), HIV, leukemia, may interfere w/ immunosuppressive therapy Interactions t Risk of disulfiram-like reaction W/ disulfiram, metronidazole T risk of exacerbation of HIV or AIDS W/ chinacea amprenavir, other protease inhibitors X effects OF azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, econazole vag cream, muromonab-CD3, mycophenolate, prednisone, tacrolimus EMS Possible immunosuppression... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (CdlCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an inactive glucuronide. 

Early clinical trials indicate that mycophenolate mofetil in conjunction with cyclosporine and corticosteroids is a more effective regimen than azathioprine in preventing the acute rejection of transplanted organs. GI side effects are most common. 

Drug interactions In a randomized, double-blind study, Zenapax or placebo was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and steroids to assess tolerability, pharmacokinetics, and drug interactions. The addition of Zenapax did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The following medications have been administered in clinical trials with Zenapax with no incremental increase in adverse reactions cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. 

Drug interactions No formal drug-drug interaction studies have been conducted. The following medications have been administered in clinical trials with Simulect with no incremental increase in adverse reactions azathioprine, corticosteroids, cyclosporine, mycophenolate mofetil, and muromonab-CD3. 

O fC U Mycophenolate Mofetil Initial dose should be given within 72 hours following transplantation 1.0 g twice a day used in combination with corticosteroids and cyclosporine... 

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. 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

The coadministration of mycophenolate mofetil with antacids results in decreased absorption. The plasma MPA concentration is significantly reduced by cholestyramine due to binding of the cholestyramine to MPAG in the intestine and interfering with the enterohepatic recirculation of the drug. The bioavailability of mycophenolate mofetil is higher when administered with tacrolimus as opposed to cyclosporine. The bioavailability of MPA is reduced by antibiotics including fluoroquinolones and metronidazole. 

Mycophenolate mofetil is used for tissue transplantation in combination with tacrolimus or cyclosporine or sirolimus plus glucocorticoids. It is used more than any other cytotoxic drug either at the time of the transplant or following the initiation of acute rejection. Mycophenolate mofetil is a prophylactic agent and cannot be used for chronic rejection or ongoing acute rejection. 

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